Synthesis, spectroscopic characterization, DFT and molecular dynamics of quinoline-based peptoids

Shahzaib Akhter; Odette Concepcion; Alexander Fernández de la Torre; Akbar Ali; Abdul Rauf Raza; Rida Eman; Muhammad Khalid; Muhammad Fayyaz ur Rehman; Muhammad Safwan Akram; Hayssam M. Ali

doi:10.1016/j.arabjc.2023.104570

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Original article

04 2023

:16;

104570

doi:

10.1016/j.arabjc.2023.104570

Synthesis, spectroscopic characterization, DFT and molecular dynamics of quinoline-based peptoids

Shahzaib Akhter^{^a}, Odette Concepcion^{^b}, Alexander Fernández de la Torre^{^c}, Akbar Ali^{^d,⁎}, Abdul Rauf Raza^{^a}, Rida Eman^{^a}, Muhammad Khalid^{^e}, Muhammad Fayyaz ur Rehman^{^a,⁎}, Muhammad Safwan Akram^{^f,^g}, Hayssam M. Ali^{^h,⁎}

a Institute of Chemistry, University of Sargodha, Sargodha 40100, Pakistan

b Departamento de Química Orgánica, University of Havana, Havana, Cuba

c Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Concepción, Concepción, Chile

d Department of Chemistry, Government College University, Faisalabad, Pakistan

e Department of Chemistry, Khwaja Fareed University of Engineering & Information Technology, Rahim Yar Khan 64200, Pakistan

f School of Health and Life Sciences, Teesside University, Middlesbrough TS1 3BX, UK

g National Horizons Centre, Teesside University, Darlington DL1 1HG, UK

h Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia

⁎Corresponding authors. akbarchm@gmail.com (Akbar Ali), fayyaz9@gmail.com (Muhammad Fayyaz ur Rehman), muhammad.fayyaz@uos.edu.pk (Muhammad Fayyaz ur Rehman), hayhassan@ksu.edu.sa (Hayssam M. Ali)

Received: 2022-10-15, Accepted: 2023-1-8,

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Peptoids mimic the functions of peptides which have a side chain appended to amidic nitrogen instead of α carbon. This structural change in their backbone gives them increased resistance from proteolysis, improved biostability, greater immunogenicity, and better bioavailability. Therefore, they are specifically designed for various biological activities, including antibacterial, antifungal, antioxidant, antifouling, and anticancer properties. The aim of the research is the one-pot synthesis of quinoline-based peptoids 5(a-b) via Ugi-4CR by the reaction of 1R-(-)-myrtenal 1, benzylamine 2, quinoline-based carboxylic acids 3(a-b), and cyclohexyl isocyanide 4. These peptoids were characterized by FT-IR, ¹H NMR, ¹³C NMR, and HR ESI-MS. In computational studies, the spectral results of 5(a-b) were compared with the calculated spectral values computed at B3LYP/6-311G (d,p) level. TD-DFT method was used to predict electron excitation of 5(a-b) and the contribution of orbitals. The electronic transition of peptoids from charge distribution was computed using natural bond order (NBO) analysis. NPA and MEP analysis was calculated to predict charge distribution in 5(a-b). The FMOs analysis was executed to calculate the global reactivity descriptor to predict the reactivity and stability of peptoids. DFT analysis showed that 5b was slightly more reactive than 5a due to extended conjugation. The biological activities were also predicted using an in silico approach that involved molecular docking and molecular dynamic (MD) simulations. The antiulcer, antibacterial, and antifungal activities were predicted based on ligand–protein binding interactions, binding energy calculations, and dissociation constants. 5(a-b) were evaluated in-vitro for anticholinesterase activity, and they showed 71% inhibition. The umbrella sampling was performed to probe ligand–protein binding.

Keywords

Peptoids

Ugi-4CR

Molecular dynamic

WHAM

Umbrella sampling

anti-cholinesterase

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1 Introduction

Multicomponent reactions (MCRs) are highly appreciated in terms of cost-effectiveness and atom economy. The product can be formed from more than two starting compounds, retaining most of the atoms of the starting compounds. MCRs use an eco-friendly synthetic approach and are completed in a very short duration (Domling et al., 2012). Among the condensation MCRs, isocyanide-based Ugi four-component reaction (Ugi-4CR) is a proficient and diverse synthetic approach. It is a highly convergent synthetic approach to prepare libraries of drug-like molecules such as peptidomimetics (Ugi, 1962; Domling and Ugi, 2000; Faldu et al., 2011 ). It is a one-pot condensation reaction of an aldehyde or a ketone, primary or secondary amine, hydrazine, or hydroxylamine (Zinner et al., 1969), an amine component, carboxylic acid, and isocyanide components (Boltjes et al., 2003). The Schiff base (imine) is formed in the first step by condensing carbonyl and amine components via hydroxyl aminal formation. The protonation of the N atom by carboxylic acid increases the electrophilicity of the C⚌N bond of imine. After the subsequent addition of carboxylate ion and isocyanide component to electrophilic iminium ion, the α-adduct is formed. Finally, the Ugi product is formed by Mumm's rearrangement (Mumm, 1910) of the α-adduct via intramolecular acylation and subsequent hydroxylamine to amide rearrangement. All the steps are in equilibrium except the last (rearrangement step), irreversible step. It is usually completed after a few minutes. Low molecular mass alcohols such as MeOH, EtOH, and CF₃CH₂OH are widely used solvents for this reaction, while polar aprotic solvents, such as DMF, CHCl₃, CH₂Cl₂, THF, and C₄H₈O₂ (dioxane) also work well.

The peptidomimetics peptoids, also called N-substituted glycine oligomers (NSGs), are bio-inspired, non-natural peptide analogues that can imitate the pharmacological activities of the peptides (Farmer and Ariens, 1982). They are generally synthesized via Ugi-4Cr (4 components) due to their high yield with water as the only by-product (Concepcion et al., 2021). In peptoids, the side chains are tethered to the amidic N instead of α‐carbon. This structural change of the backbone of the peptide skeleton makes them resistant to proteolytic enzymes (Webster and Cobb, 2018). They also show low immunogenicity and better cell permeability as compared to peptides (Kwon and Kodadek, 2007). However, they are structurally labile due to the absence of hydrogen on amidic N, which could lead to the formation of a repeating secondary structure. The flexible structure of peptoids can be stabilized by steric or electronic interactions of bulky side chains in peptoids that could form a helical secondary structure (Armand et al., 1998; Kirshenbaum et al., 1998). They exhibit conformational heterogeneity due to the cis and trans isomerization of the tertiary amide (Sui et al., 2007).

The derivatives of peptoids have been reported to display various biological properties such as antibacterial (Goodson et al., 1999), antifungal (Ryge et al., 2008), anti-inflammatory (García-Martínez et al., 2002), anticancer (Krieger et al., 2017), antimalarial (Diedrich et al., 2018) and neuroprotective (Malet et al., 2006). They were also assessed as antifouling agents (Statz et al., 2008), contrast agents for MRI (Haynes, 2008), lung surfactants (Brown et al., 2008), transfection agents (Murphy et al., 1998), enantioselective catalysts (Maayan et al., 2009) and antiviral agents (Hamy et al., 1997). Peptoids have also been used to stabilize nanoparticles (Robinson et al., 2011) and segregate DNA sequences (Haynes et al., 2005).

The quinoline-based active synthetic heterocyclic compounds have a broad spectrum of pharmacological and biological properties, including antiproliferative (Ferlin et al., 2001), anti-inflammatory (Chen et al., 2003), antimalarial (Park et al., 2002), antimicrobial (Nandhakumar et al., 2007) and antitumor (Kuo et al., 1993; Xia et al., 1998) activities. The research method for this study aimed to design novel heterocyclic compounds which retain the quinoline nucleus, preserving its structural activity-defining features (Silverman and Holladay, 2014). Henceforth, the synthesis of novel quinoline-based peptoids via Ugi-4CR is presented with an evaluation of their pharmacological and biological activity. Introducing quinoline moiety in the peptoid backbone results in a helical structure that increases its permeability in the cell system. Because at least 50 % alpha-chiral, aromatic residues are necessary for the stable helical structure in peptoids (Wu et al., 2001). Therefore, the Ugi-4CR method was employed to prepare target peptoids with efficacy using reagents such as aromatic aldehyde, isocyanide, and quinoline-based carboxylic acid. Then in-silico method, molecular docking, and molecular dynamics were used to evaluate their biological activity against selected proteins.

2 Experimental

2.1

2.1 General experimental

The novel quinoline-based peptoids were synthesized as targeted compounds for the desired evaluation. The experiments were carried out with analytical-grade reagents and solvents without additional purification. The TLC was used to track the reaction's progress using the Merck Supelco TLC Silica gel 60 F254 plates. The Bruker-Avance A-V (400/100 MHz for ¹H and ¹³C NMR, respectively) spectrometer was used to record NMR spectra in CDCl₃ as solvent. The chemical shifts (δ) and coupling constants (J) are designated with ppm and Hz units. The FTIR analysis was carried out on the Shimadzu IR Prestige-21 instrument. High-resolution mass spectra (HRMS) were recorded using electron spray ionization (ESI) (Hybrid linear ion trap–orbitrap FT-MS and QqTOF/ MS–Microtof–QII models).

2.1.1

2.1.1 General procedure for the synthesis of N-benzyl-N-[(2́-(cyclohexylamino)-1́-{(1́́S, 5́́R)-6́́,6́́-dimethylbicyclo[3.1.1]hept-2́́-en-2́́-yl}-2́-oxoethyl)]quinoline-2-carboxamide (5a)

A mixture of (1R)-(-)-myrtenal 1 (97 %, 152 µL, 1.0 mmol, 1.0 equiv.), benzylamine 2 (130 µL, 1.2 mmol, 1.2 equiv.), quinoline-2-carboxylic acid 3 (207.66 mg, 1.2 mmol, 1.2 eq.) and cyclohexyl isocyanide 4 (µL, 1.0 mmol, 1.0 eq.) were stirred in MeOH (5 mL) at room temperature for 24 h. The flash chromatography was used to purify the target peptoid using n-hexane / EtOAc (1:1). The targeted compound 5a was obtained as pale yellow amorphous solid (315 mg, 50 %).

ύ_max (cm⁻¹, as KBr disc): 3327 (amidic, non H-bonded N—H), 3055 (amidic, H-bonded N—H), 1673 (amidic, non-conjugated C⚌O), 1620 (amidic, conjugated C⚌O), 1150 (conjugated C⚌N); δ_H (ppm): 1.13 (2H, m), 1.27 (6H, m), 1.30 (4H, m), 1.60 (2H, m), 1.80 (4H, m), 2.06 (1H, m), 2.18 (1H, m), 2.34 (2H, m), 4.01(1H, m), 5.81 (1H, m), 6.22 (1H, d, J = 8.0 Hz), 7.12 (2H, m), 7.24 (1H, m), 7.61 (1H, m), 7.72 (2H, m), 7.74 (1H, m), 7.88 (1H, dd, J = 8.0, 4.0 Hz), 8.07 (1H, d, J = 8.0 Hz), 8.21 (1H, m) and 8.48 (1H, m); δ_C (ppm): 21.0, 21.3, 24.1, 24.9, 25.7, 26.2, 31.7, 34.6, 40.4, 52.4, 66.6, 121.5, 124.8, 126.7, 127.1, 128.0, 128.1, 128.3, 128.5, 128.6, 128.8, 130.5, 130.7, 140.9, 141.5, 155.3, 166.9 and 170.5; HR ESIMS m/z: Calculated for C₃₄H₃₉N₃O₂, 544.2934 [M + Na]⁺, 522.3078 [M + H]⁺ amu.

2.1.2

2.1.2 General procedure for the Synthesis of N-benzyl-N-[(2́-(cyclohexylamino)-1́-{(1Ś́,5́́R)-6́́,6́́-dimethylbicyclo[3.1.1]hept-2́́-en-2́́-yl)}-2́-oxoethyl)]quinoline-6-carboxamide (5b)

The same procedure was used to synthesize the targeted peptoid 5b, in which quinoline-6-carboxylic acid 3 (208 mg, 1.2 mmol, 1.2 eq.) was used. The targeted peptoid was obtained as a white amorphous solid (345 mg, 55 %) after flash chromatography using n-hexane / EtOAc (1:1) gradient (Scheme 1).

ύ_max (cm⁻¹, as KBr disc): 3313 (amidic, non H-bonded —N—H), 3026 (amidic, H-bonded N—H), 1671 (amidic, non-conjugated C⚌O), 1627 (amidic, conjugated C⚌O), 1538 (conjugated —C⚌N); δ_H (ppm): 1.17 (2H, m), 1.21 (4H, m), 1.32 (4H, m), 1.71 (6H, m), 1.89 (2H, m), 2.11 (1H, m), 2.33 (2H, m), 2.45 (1H,m), 3.75 (1H, m), 4.67 (1H, m), 5.73 (1H, s), 7.23 (2H, m), 7.33 (2H,m), 7.42 (1H,m), 7.42 (1H, m), 7.89 (1H, m), 7.93 (1H, m), 8.00 (1H, m), 8.15 (1H, m), 8.42 (1H, m) and 8.95 (1H, m); δ_C (ppm): 21.1, 24.9, 25.6, 26.1, 26.3, 31.8, 33.0, 38.1, 40.4, 44.6, 48.7, 121.9, 124.5, 125.3, 126.4, 126.7, 127.3, 127.6, 127.8, 128.6, 128.7, 134.5, 136.6, 136.7, 148.5, 151.6, 167.5 and 173.1; HR ESIMS m/z: Calculated for C₃₄H₃₉N₃O₂, 560.2850 [M + K⁺], 544.2934 [M + Na]⁺, 522.3078 [M + H]⁺ amu.

2.2

2.2 Computational procedures

2.2.1

2.2.1 DFT calculations

The Gaussian 09 W program package was used to compute all the quantum chemical calculations (Frisch et al., 2013) on a Dell Workstation 7810 with 64 GB Ram and a GEForce RTX 2080Ti graphic accelerator. The molecular geometries of quinoline-based peptoids (5a-b) were fully optimized using a DFT approach with B3LYP/6-311G (d,p), allowing the computation of the theoretical vibrational spectra. The vibrational modes were assigned using the potential energy distribution (PED) of the VEDA (Vibrational Energy Distributional Analysis) program (Jamroz, 2004). The NBO 3.1 program (Glendening et al., 2003) was used to compute the natural bond orbital (NBO) at the B3LYP/6-311G (d,p) level to determine intermolecular delocalization or hyperconjugation by second-order interactions between occupied orbitals and vacant orbitals of the system. Time-dependent DFT (TD-DFT) at the B3LYP/6-311G (d,p) level was used to calculate the electronic transitions, vertical excitation energies, absorbance, oscillator strengths, and UV–visible spectra. The electronic properties, such as the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO), were computed using the TDDFT approach. The calculations for nonlinear optical (NLO) analysis of 5(a-b) were done to calculate electronic dipole moment (μ), linear polarizability (α), and first-order hyperpolarizabilities (β). The reactive sites of 5(a-b) were predicted by calculating molecular electrostatic potential (MEP) at B3LYP/6-31G(d,p) level (Fig. S7). Avogadro (Hanwell et al., 2012) and GaussView 6.0 (Dennington et al., 2016) were used to create input files. The analysis of output files was done using GaussSum (O'Boyle et al., 2008), Multiwfn (Lu, 2015), and ChemCraft (Zhurko and Zhurko, 2009).

2.3

2.3 The In-silico studies

The biological activities such as antioxidant, antibacterial, antifungal, and antiviral properties were predicted by screening 5(a-b) against the selected proteins using a modified method for inverse docking module in YASARA (Yet Another Scientific Artificial Real Application) software version 20.7.4 (Krieger and Vriend, 2014). Protein structures were obtained from the Protein Data Bank (https://www.rcsb.org/). AutoDock LGA module and AMBER03 forcefields in YASARA with 100 global docking runs and 1000 random seed values were used for docking (Bilal et al., 2021; Rehman et al., 2021). Finally, the docked 5(a-b) were rescored using AutoDock local search (LGA-LS) method in YASARA.

The docking scoring and rescoring were completed by following empirical Eq. (1)

(1)

Δ G = {Δ G}_{(V a n d e r W a a l)} + {Δ G}_{(H - b o n d i n g)} + {Δ G}_{(e l e c t r o s t a t i c)} + {Δ G}_{(t o r s i o n a l f r e e e n e r g y)} + {Δ G}_{(d e s o l v a t i o n e n e r g y)}

The LigPlus (Laskowski and Swindells, 2011) and PyMOL (DeLano, 2002) were used to extract the lowest energy binding energy docking poses, and ligand–protein interactions were mapped. Molecular Dynamic simulations (MDS) were performed in YASARA ver. 20.7.4 using AMBER14 as a forcefield, pH 7.4 (set constant using 0.9 % NaCl), 298 K temperature, and a density of 0.997 g/mL as described (Fernandez-Poza et al., 2021). A 20 Å water-filled simulation cell was used to place the protein–ligand complex, while simulation time steps were calculated after 2.50 fs. 10–30 ns simulations were calculated to analyse the obtained data. The ADME (absorption, digestion, metabolism, and excretion) properties of 5(a-b) were predicted using the online server SwissADME (Daina et al., 2017) (https://www.swissadme.ch/).

2.3.1

2.3.1 Umbrella sampling of 5(a-b)-AchE complex

The ligand–protein bindings for the AChE-5(a-b) complex were probed by umbrella sampling performed using YASRA dynamics (Krieger and Vriend, 2014) and the weighted histogram analysis method (WHAM)(Kumar et al., 1992). A 100 ns MD simulation were run with 15 windows to sample ligand position in term of protein. WHAM scripts for YASARA were provided by Dr Silva (Silva and Silva, 2021), where 5.0 kcal/mol/Å² force constant, 5 ns in each bin (size 0.2 Å apart) data was collected, and potentials of mean force were calculated and plotted.

3 Results and discussion

In the first step, the Schiff base (Z)-N-benzyl-1-((1S,5R)-6,6-dimethylbicyclo [3.1.1]hept-2-en-2-yl)-methan imine was synthesized by coupling of benzylamine 1 and (1R)-(-)-myrtenal 2 in a polar solvent (MeOH). In the next step, the reaction mixture was added to quinoline-based carboxylic acid 3 and isocyanocyclohexane 4. The carboxylic acid protonates the Schiff base, which generates an iminium ion. Then the addition of carboxylate ion to the iminium ion afforded an α-adduct. After Mumm rearrangement of this α-adduct targeted peptoids, 5(a-b) were formed (Scheme 1).

Spectroscopic techniques such as FTIR, NMR, and ESI MS were used to characterize the targetted peptoids 5(a-b). In the FT-IR spectrum of 5a, the appearance of a medium peak at 3328 (non-H-bonded) confirmed the presence of the amidic N—H group. The strong absorbance peaks at 1673 and 1620 cm⁻¹ confirmed the presence of the amidic carbonyl functional group. Another absorbance signal at 1550 cm⁻¹ indicates the presence of a C⚌C bond (isoquinolinic moiety) (Fig. S1). Almost similar patterns were observed in the IR spectrum of 5b with slightly different absorbance values but conforming to the same functional groups (Fig. S2).

The ¹H NMR of both 5a-b (Fig. S3 & S5) showed a jungle of proton signals (mostly as multiplets) in the aliphatic (¹H attached to sp³ carbons) region (1.0 to 2.5 ppm) and aromatic (¹H attached to sp² carbons) region (7.0 to 8.5 ppm) (Fig. S3 and S4). The only olefinic ¹H (attached to C³′) of 5a appeared (at 6.22 ppm) as a clear doublet (J = 4.0 Hz), which confirms the presence of myrtenal moiety in the peptoid. The presence of multiplet signals (11H integration) in the aromatic region also confirms the presence of quinolone (benzo-1-azine) and phenyl moieties in 5a (Fig. S3). The presence of two carbon signals, at 166.9 and 170.5 ppm in 5a (Fig. S4) and 167.5 and 173.1 ppm in 5b (Fig. S6), in the broadband ¹³C NMR of both 5a-b indicates the presence of two amidic carbonyl carbons (Fig. S4 and S6). The ESI MS of both 5a and 5b showed [M + Na] ions at 544.2937 (Figs. 1 and S6) and 544.2933 amu, which is in good agreement with calculated values (544.2935 and 544.2934 amu, respectively) with a low molecular mass difference (0.2 and 0.1 amu difference, respectively).

3.1

3.1 DFT study

The computational studies of novel synthesized compounds 5(a-b) are calculated and discussed using Lee–Yang–Parr B3LYP/6-311G (d,p) level basic set of DFT analysis in this section.

3.1.1

3.1.1 Vibrational analysis

The experimental FTIR bands were compared with relative intensities and band assignment of 5(a-b), computed at DFT/B3LYP/6-311G (d,p) level to predict the intensity and vibrational modes (Table S1 and S2). The theoretical DFT values were scaled to experimental data by a factor of 0.97, compensating for systematic errors introduced by the incompleteness of the basis set, lack of electron correlation, and vibrational anharmonicity (Andrade et al., 2008; Vennila et al., 2021; Raja et al., 2022 ). The modes of vibration in spectral studies are as follows:

3.1.1.1

3.1.1.1 C—H vibrations

The aromatic region for C—H stretching vibrations is normally found between 3000 and 3100 cm⁻¹ (Muthukkumar et al., 2018), while the vibrations for cyclohexane C—H stretching are observed at 3000–2840 cm⁻¹ (Chen et al., 2012). For aromatic C—H bonds, scissoring and rocking (in-plane bending) vibrations are found between 1300 and 1000 cm⁻¹, while twisting and wagging (out-of-plane bending) vibrations are found between 750 and 1000 cm⁻¹. The scissoring vibration of C—H of cyclohexane is found at 1468 cm⁻¹ (Silverstein and Bassler, 1962). For 5a, the symmetric C—H stretching vibration in aromatic and quinoline aromatic rings was located at 3124–3052 cm⁻¹. The asymmetric stretching C—H vibrations were located at 3099, 3085, and 3070 cm⁻¹. The scissoring and rocking stretching vibrations were situated at 1481, 1282, 1235, 974, 970, and 963 cm⁻¹, respectively. Furthermore, stretching symmetric and asymmetric modes of vibration were observed at 3046–2966 cm⁻¹ for cyclohexane. The scissoring and rocking vibrations for myretenal and cyclohexane scaffold were observed at 1473–1429 cm⁻¹. The only experimental value of 1463 cm⁻¹ was correlated with 1468 cm⁻¹ (DFT calculation) of C—H of myretenal (Table S1). For 5b, C—H symmetric and asymmetric stretching vibrations were found between 3075 and 2885 cm⁻¹. These DFT values were correlated with experimental values of 3026, 2927, and 2857 cm⁻¹. While scissoring and rocking vibrations of 5b were observed at 1475 and 1469–1450 cm⁻¹ (Table S2).

3.1.1.2

3.1.1.2 C⚌C stretching vibration

The stretching vibration for the C⚌C bond is usually found between 1660 and 1600 cm^−1, while for the aromatic system, it is found between 1600 and 1475 cm⁻¹ (Pavia et al., 2014). For 5a, the symmetric and asymmetric C⚌C stretching vibrations were situated between 1595 and 1489 cm⁻¹. These DFT calculations were in accordance with one experimental value of 1550 cm⁻¹. Furthermore, in-plane bending vibrations were observed at 1481, 1331, 1235, and 974 cm⁻¹ (Table S1). For 5b, the symmetric and asymmetric C⚌C stretching vibrations were located at 1581–1536, 1473, 1333, 1180, 1172, and 1065 cm⁻¹, which was experimentally correlated with 1538 cm⁻¹. The in-plane bending vibrations of C⚌C—H were observed at 1473, 1438, 1436, 1403, 1317, 1315, 1217, 1137, and 1108 cm⁻¹ (Table S2).

3.1.1.3

3.1.1.3 C—C stretching vibration

The stretching vibrations of the C—C bond usually occur at 1650–1400 cm⁻¹ of the IR spectrum (Lin-Vien et al., 1991; Sathiyanarayanan, 2004). For 5a, symmetric and asymmetric C—C stretching vibrations were located at 1183, 1154, 1121, 1102, 941, 903, 843, 835, 823, 815, and 809 cm⁻¹ (DFT) which is experimentally correlated with the values of 1216, 1154, and 827 cm⁻¹, respectively (Table S1). For 5b, symmetric and asymmetric C—C stretching vibrations were observed at 1195, 992, 894, 870, and 862 cm^−1, which were in agreement with experimental values of 1197, 988, and 893 cm⁻¹ (Table S2).

3.1.1.4

3.1.1.4 C⚌O vibration

The C⚌O stretching vibration is normally found between 1850 and 1600 cm⁻¹ (Colthup et al., 1964). For 5a, the nonconjugated C⚌O vibration was observed at 1678 cm⁻¹ (DFT) which corresponds well with the experimental value of 1673 cm⁻¹. In contrast, conjugated C⚌O band wavenumber was observed at 1626, which is experimentally correlated with the value of 1620 cm⁻¹ (Table S1). For 5b, C⚌O vibrations were located at 1628 (non-conjugated) and 1584 cm⁻¹ (conjugated), which were in close accordance with the experimental value of 1671, 1627 cm⁻¹ (Table S2).

3.1.1.5

3.1.1.5 N—H vibrations

The region around 3300–3600 cm⁻¹ is generally specific for N—H vibrations (Wiles and Suprunchuk, 1969; Puviarasan et al., 2002). For 5a, N—H vibration was found at 3473 cm⁻¹ (DFT), supporting the experimental value of 3328 cm⁻¹. In comparison, bending vibrations of the N—H band were located at 570, 521, 516, 474, and 454 cm⁻¹ (Table S1). For 5b, N—H vibration was located at 3453 cm⁻¹, correlated with the experimental value of 3313 cm⁻¹.

3.1.1.6

3.1.1.6 C—N vibrations

The vibrations at 1500–500 cm⁻¹ are generally observed for the C—N bond (Dede et al., 2018). The stretching vibrations for C—N were observed at 1455, 1411, 1368, 1352, 1183, 1154, and cm^−1, supporting one experimental value of 1154 cm⁻¹. The bending vibrations of C—C—N were observed at 695, 660, 652, 599, and 570 cm⁻¹, in accordance with the experimental value of 709 cm⁻¹ (Table S1). For 5b, C—N stretching vibrations were observed at 1378, 1229, 1130, and 532 cm^−1, whereas bending vibrations were observed at 1443, 1408, 1129, 603, 573, and 494 cm⁻¹, supporting one experimental value of 1409 cm⁻¹ (Table S2).

3.1.2

3.1.2 UV–visible analysis

The electronic excitations of 5(a-b) were calculated using theoretical UV–visible spectral analysis at TD-DFT/B3LYP/6-311G (d,p) level. It can be observed that 5a showed a little higher absorption than 5b (Fig. 2). The reason for the higher absorption of 5a is that the carbonyl group and nitrogen of the quinoline moiety nucleus are conjugated.

Theoretical UV–Visible Spectrum of 5(a-b) at B3LYP/6-311G (d,p) level.

The wavelengths of maximum absorption (λ^max), excitation energies (E), oscillator strengths (f), as well as the major and minor orbitals contributions based on the TD-DFT method, have been listed in Table 1.

Table 1 Excitation energies, wavelengths, and oscillator strengths of 5(a-b).

Comp.	DFT $λ$ (nm)	E (cm⁻¹)	f	MO contributions
5a	330	30,259	0.0037	H-1 $\to$ L (69 %), H-8 $\to$ L (4 %), H-7 $\to$ L (5 %), H-6 $\to$ L (6 %), H-4 $\to$ L (7 %), H-3 $\to$ L (4 %)
	315	31,718	0.0167	H $\to$ L (93 %), H-4 $\to$ L (2 %)
	302	33,072	0.0094	H-3 $\to$ L (21 %), H-2 $\to$ L + 1 (51 %), H-1 $\to$ L (12 %), H-8 $\to$ L (2 %), H-4 $\to$ L (9 %)
5b	314	31,824	0.0109	H $\to$ L (92 %), H-1 $\to$ L (3 %)
	298	33,578	0.0153	H-1 $\to$ L (85 %), H-2 $\to$ L (6 %), H $\to$ L (3 %)
	294	33,983	0.0015	H-7 $\to$ L (87 %), H-2 $\to$ L + 2 (10 %)

H = HOMO, L = LUMO, Expt = experimental, f = Oscillator strength, E = energy, and MO = molecular orbital.

The electronic transition explaining the contribution of molecular orbitals can be assessed by the HOMO and LUMO contributions. In 5a, there are 3 major absorption peaks. For 5a, the strongest absorption was calculated at 330 nm with 0.0037 cm⁻¹ oscillator strength. The largest contribution of 69 % was found between HOMO-1 and LUMO.

3.1.3

3.1.3 Natural bond orbital (NBO) analysis

The well-explained information about intra-/inter-molecular bonding, interactions, and charge transfer or hyperconjugative interactions in the bonding and antibonding orbitals is given by NBO analysis (Weinhold et al., 2016). The stabilization energy (E²) is used to study the interactions of bonding and antibonding orbitals. The E² can be calculated using a second-order perturbation approach using the formula given in Eq. (2) (Muthu and Ramachandran, 2014).

(2)

E^{(2)} = q_{i} \frac{{(F_{i, j})}^{2}}{ε_{j} - ε_{i}}

Here, F(i.j)² = the fock matrix element between i and j NBO orbitals, q_i = population of the donor orbital, and $ε$ _j, $ε$ _i = energies of NBO's (Liu et al., 2005). A more detailed explanation of the NBO analysis for 5(a-b) is found in Table S3 and S4. However, Table 2 summarizes some representative values.

Table 2 NBO analysis of 5(a-b).

Comp	Donor(i)	Types	Acceptor(i)	Types	E(2) (kJ/mol)	E(j)E(i) (a.u)	F(i,j) (a.u)
5a	C7-C13	Σ	C3-C7	σ*	6.17	1.03	0.071
	C34-C35	Π	C30-N31	π*	23.78	0.28	0.074
	C24-C29	Π	C27-C28	π*	21.82	0.27	0.069
	C27-C28	Π	C25-C26	π*	20.78	0.28	0.069
	C24-C29	Π	C25-C26	π*	20.74	0.28	0.068
	N2	LP(1)	C1-O18	π*	47.42	0.31	0.109
	N5	LP(1)	C4-O8	π*	67.26	0.27	0.121
	O8	LP(2)	C4-N5	σ*	22.16	0.74	0.116
	O18	LP(2)	C1-N2	σ*	21.78	0.72	0.113
5b	C9-C14	Σ	C10-C16	σ*	5.87	0.94	0.066
	C36-C37	Π	C38-N39	π*	23.72	0.28	0.073
	C24-C29	Π	C27-C28	π*	20.74	0.28	0.068
	C25-C26	Π	C24-C29	π*	20.29	0.29	0.069
	C27-C28	Π	C25-C26	π*	20.28	0.28	0.068
	N5	LP(1)	C4-O8	π*	68.27	0.27	0.121
	N2	LP(1)	C1-O18	π*	44.65	0.32	0.108
	O18	LP(2)	C1-N2	σ*	21.97	0.7	0.094
	O8	LP(2)	C4-N5	σ*	21.6	0.73	0.114

E⁽²⁾ = stabilization energy (hyper conjugative interaction energy), E(j)-E(i) = the energy difference between donor and acceptor i and j NBO orbitals, and F(i, j) = the Fock matrix element between i and j NBO orbital.

For 5a, the strongest conjugative n-π* interactions were developed due to resonance between electron donor LP (1)N5 and antibonding acceptor π*C4-O8 and π*C4-O8 with stabilization energies of 67.26, and 47.42 kj/mol. Similarly, another important hyperconjugative n-σ* transition was developed between electron donor LP(2)O8 and σ*C4-N5 (E² = 22.16 kj/mol), whereas for LP(2)O18, the same transitions was developed with antibonding acceptor σ*C1-N2 (E² = 21.78 kj/mol). Moreover, some prominent intramolecular hyperconjugative π-π* transitions were formed by the overlap of the orbitals between πC34-C35 → π*C30-C31 (quinoline moiety), πC24-C29 → π*C27-C28, πC27 → C28 → π*C25-C26, πC24-C29 → π*C25-C26 (benzene ring) with energies as 23.78, 21.82, 20.78, and 20.74 kj/mol, respectively. The σ-σ* interactions were formed between σC7-C13 → σ*C3-C7 with the minimum stabilization energy of 6.17 kj/mol. While intramolecular hyperconjugative interaction between πC30-N31 → π*C1-O18 and πC1-O18 → π*C30-N31 with 9.4 and 3.86 kj/mol stabilization energies, respectively, predicted the conjugation between the carbonyl group and quinoline ring (Table 2 and Fig. 3).

For 5b, the most important conjugative n-π* interaction was formed due to resonance between electron donor LP(1)N5 and electron acceptor π*C4-O8 (E² = 68.27 kj/mol). A similar interaction was also between electron donor LP(1)N2 and electron acceptor π*C4-O8 (E² = 44.65 kj/mol). Whereas, the hyperconjugative LP-σ* transition was formed between electron donor LP(2)O18 and electron acceptor σ*C1-N2 (E² = 22.97 kj/mol) and also between electron donor LP(2)O8 and electron acceptor σ*C4-N5 (E² = 21.6 kj/mol). Furthermore, some prominent intramolecular hyperconjugative π-π* transitions were developed between πC36-C37 → π*C38-C39 (quinoline moiety), πC24-C29 → π*C25-C26, πC24-C29 → π*C27-C28, πC25-C26 → π*C24-C29 (benzene ring) with stabilization energies of 23.72, 20.8, 20.74, and 20.29 kj/mol, respectively. Furthermore, σ-σ* interaction was developed between σC7-C13 → σ*C10-C16 with minimum stabilization energy of 5.87 kj/mol (Table 2 and Fig. 3).

3.1.4

3.1.4 Natural population analysis (NPA)

Natural population analysis (NPA) can precisely predict the distribution of electrons in various subshells of atomic orbitals of the compounds under study (Gunasekaran et al., 2008).

In 5a, all the hydrogen atoms were positively charged, while all carbon atoms except C1, C4, C30, and C32 were negatively charged. The positive charge on C1 and C4 is due to bonding to an electronegative oxygen atom. Similarly, C30 and C32 are positively charged due to their bond with a nitrogen atom in the quinoline nucleus. It was found that the most electronegative charge of −0.65758e and −0.65473e is collected on O8 and O18. While the most electropositive charge of 0.71481e and 0.68961e accumulated on C4 and C1 (Fig. 4). In 5b, all the hydrogen atoms were positively charged, while all carbon atoms except C1, C4, C33, and C38 were negatively charged. The higher electronegative charges, −0.6658e and −0.63771e, accumulated on O8 and N5, while the C4 and C1 (electrophilic centre) have the highest electropositive charges of 7169e and 0.6942e (Fig. 4).

Natural populational analysis of 5(a-b).

3.1.5

3.1.5 Molecular electrostatic potential (MEP) analysis

The molecular electrostatic potential (MEP) tool is used to visualize areas of reactivity toward nucleophiles and electrophiles in addition to charge density distribution, shape, size, and site of chemical reactivity (Murray and Sen, 1996). The MEP surface was calculated at B2LYP/6–311 (d,p) optimized geometry. The red, blue, and yellow colours on the MEP surface represent electron-rich (partially negative charge), electron-deficient (partially positive charge), and slightly electron-rich regions, respectively, as shown in Fig. 5. The negative charge was mainly localized on oxygen atoms of the amidic group and the nitrogen of quinoline moiety in 5a, while comparatively low electron density was found in the nitrogen atom in the quinoline ring of 5b. The low negative charge in 5b was due to the direct conjugation of the nitrogen atom of the quinoline ring, the carbonyl group of the amidic group, which subsequently decreased the amount of the negative charge. However, in 5a, the lone pair on the nitrogen atom in the quinoline ring is primarily localized in the ring. The hydrogen atoms of the aromatic and quinoline rings possessed positive charge on the MEP surface. These positive and negative sites in 5(a-b) are the reason for the chemical behaviour of compounds and can be used to explain biological interactions.

3.1.6

3.1.6 Frontier molecular orbital (FMO) analysis

The highest occupied molecular orbitals (HOMO) and the lowest unoccupied molecular orbitals (LUMO) are an important part of DFT analysis and are named frontier molecular orbitals (FMOs). Th FMOs analysis effectively explains molecular interactions and charge transfer between HOMO and LUMO of the compounds (Ali et al., 2020). The FMOs are also used to assign chemical reactivity, kinetic stability, and optical polarizability of the materials (Asiri et al., 2011).

The FMOs of 5(a-b) were calculated at B3LYP/6-311G (d,p) level to determine energy gaps (ΔE) between FMOs by the electron distribution from HOMO, HOMO-1, and HOMO-2 to LUMO, LUMO + 1, and LUMO + 2; were listed in Table 3. For 5a, the charge density in HOMO was distributed across the benzene ring, myrtenal, and carbonyl groups, whereas the charge density in LUMO was concentrated on the quinoline ring conjugated to the carbonyl group. Likewise, the charge density in HOMO for 5b was spread over myrtenal and carbonyl groups, while the charge density in LUMO was spread over the quinoline group.The low energy gap reflects higher reactivity and low stability of the compound; in contrast, the higher energy gap reflects low reactivity and high stability of the compound (Abou-Rachid et al., 2008). The energy gap (ΔE_HOMO-LUMO) was slightly lower in 5b (4.37 eV) compared to 5a (4.45 eV). Therefore, it was assumed that 5b was slightly less stable and more reactive (Fig. 6).

Table 3 The E_HOMO, E_LUMO, and energy gap of 5(a-b) at B3LYP/6-311G (d,p) level.

5a			5b
MO_(S)	E(eV)	Δ E (eV)	MO_(S)	E(eV)	Δ E (eV)
HOMO	−6.34	4.45	HOMO	−6.21	4.37
LUMO	−1.89	4.45	LUMO	−1.85	4.37
HOMO-1	−6.36	5.33	HOMO-1	−6.49	5.48
LUMO + 1	−1.03	5.33	LUMO + 1	−1.01	5.48
HOMO-2	−6.57	6.32	HOMO-2	−6.61	6.17
LUMO + 2	−0.25	6.32	LUMO + 2	−0.4	6.17

MO = molecular orbital, ΔE (eV) = Energy gap between HOMO and LUMO.

Frontier molecular orbitals of 5(a-b). The red and green colour represents positive and negative phases, respectively, at B3LYP/6-311G (d,p) level.

The energies of HOMO and LUMO were used to calculate molecular properties such as ionization potential, electron affinity, hardness, softness, and chemical potential of 5(a-b), defined by Koopman's theoram (Periyasamy et al., 2021; Venkatesh et al., 2022).

The electron affinity (A) and ionization potential (I) were calculated using Eqs. (3) and (4) (Fukui, 1982).

(3)

I = {- E}_{HOMO}

(4)

A = {- E}_{LUMO}

Here, global hardness (η) and, electronegativity (X), chemical potential (μ) (Parr et al., 1978) were obtained using Eqs. (5), (6), and (7).

(5)

η = \frac{I - A}{2}

(6)

X = \frac{I + A}{2}

(7)

μ = - \frac{I + A}{2}

The electrophilicity(ω) was calculated to determine charge transfer in 5(a-b) by using Equation (8) (Chattaraj and Roy, 2007; Tandon et al., 2020).

(8)

ω = \frac{μ^{2}}{2 η}

The global softness (σ) could be calculated by using Eq. (9).

(9)

σ = \frac{1}{2 η}

All the calculated values of ionization potential (I) and electron affinity (A), global hardness (η) and electronegativity (X), chemical potential (μ), electrophilicity(ω), and global softness (σ) are listed in Table 4.

Table 4 The calculated molecular descriptors of 5(a-b) at B3LYP/6-311G (d,p) level.

Compound	I	A	X	η	μ	ω	Σ
5a	6.34	1.89	4.12	2.23	−4.12	3.81	0.225
5b	6.21	1.85	4.03	2.18	−4.03	3.72	0.229

Ionization potential (I), electron affinity (A), electronegativity (X), global hardness (η), chemical potential (μ), global electrophilicity (ω), and global softness (σ).

The electron-donating and accepting abilities were described by ionization potential and electron affinity. The ionization potential and electron affinity are used to understand the capacity of electron-donating and accepting. In the studied molecules, the ionization potential was significantly higher than electron affinity (A) values. Therefore, it could be assumed that peptoids 5(a-b) are a better electron donor. The 5a was found to have a slightly greater ionization potential (I) and electron affinity (A) than 5b, indicating that it is a better electron donor in comparison. The global hardness was determined to be [5a (η = 2.225 eV)] > [5b (η = 2.184 eV)], which explained that 5a is more stable and less reactive than 5b. Additionally, a slightly higher chemical potential (μ) and global softness (σ) value for 5b than 5a shows that 5b is more reactive and less stable (see Table 5).

Table 5 Calculated NLO parameters; the average linear polarizability (α), the anisotropy of polarizability (Δα), and the first hyperpolarizability (β) for 5(a-b).

Parameters	Peptoids
Parameters	5a	5b
μ_x^a	−0.03	0.58
μ_y^a	−0.06	−0.25
μ_z^a	−0.41	−0.19
μ_total^a	0.42	0.66
α_xx^b	483.35	452.03
α_xy^b	−14.23	−3.73
α_yy^b	422.95	371.17
α_xz^b	2.88	18.10
α_yz^b	15.34	−7.34
α_zz^b	286.33	302.12
α_mean^b	397.54	375.11
Δα^c	133.49	119
β_xxx^b	−409.72	293.31
β_xxy^b	−42.96	−4.77
β_xyy^b	87.91	93.61
β_yyy^b	38.12	14.33
β_xxz^b	33.46	83.12
β_xyz^b	78.02	23.67
β_yyz^b	17.45	−42.69
β_xzz^b	−59.88	−14.48
β_yzz^b	−6.85	12.68
β_zzz^b	46.75	38.24
β_total^b	394.15	381.31

a in Debye.

b in atomic units (a.u).

c in Å³.

3.1.7

3.1.7 Nonlinear optical (NLO) properties

Nowadays, organic compounds are explored due to their low cost, tunable absorption spectra, and significant nonlinear response (Murugavel et al., 2016). Electronic properties are considered to be responsible for the strength of the optical response, which in turn depends on the total molecular dipole moment (µ), linear response (polarizability, α), and nonlinear responses (hyperpolarizabilities, β, and γ) (Peng and Yu, 1994; Tsutsumi et al., 1998; Breitung et al., 2000 ). NLO parameters of 5(a-b) were calculated at the B3LYP/6-311G (d,p) level.

The total static dipole moment (µ), average polarizability (α), and first-order hyperpolarizability (β) were calculated using Eqs. (10), (11), and (12).

(10)

μ_{total} = {(μ_{x^{2}} + μ_{y^{2}} + μ_{z^{2}})}^{\frac{1}{2}}

(11)

α_{mean} = \frac{1}{3} (α_{xx} + α_{yy} + α_{zz})

(12)

β_{total} = {[{(β_{xxx} + β_{yyx} + β_{zzx})}^{2} + {(β_{yyy} + β_{xxy} + β_{zzy})}^{2} + {(β_{zzz} + β_{yyz} + β_{xxz})}^{2}]}^{\frac{1}{2}}

3.2

3.2 The In-silico studies

The molecular docking study of 5(a-b) shows that 5a strongly interacts with gastric H⁺, K⁺ ATPase (PDB ID: 2XZB) in the luminal cavity (Abe et al., 2011) with a binding energy of −11.24 kcal/mol and a dissociation constant of 5.73 nM (Fig. 7). The active site residues include Gln¹²⁷, Leu¹³³, Tyr³²⁴, Arg³²⁸, Ala³³⁵, Tyr⁷⁹⁹, Tyr⁸⁰², Leu⁸⁰⁹, Cys⁸¹³, Trp⁸⁹⁹, and Glu⁹⁰⁰ (Table S6). The 5b occupies the same binding pocket in the enzyme with a binding energy of −11.06 kcal/mol and a dissociation constant of 7.8 nM (Table S7). A hydrogen bond (3.25/3.30 Å) was observed between the hydroxyl of Tyr⁸⁰² and with N2 of 5(a-b), while other residues stabilize the protein–ligand complex by hydrophobic interactions (Fig. 7c-f).

5(a-b) complex with H+, K + ATPase (a, d) Electrostatic surface for ligand–protein complex, (b & c) enzyme-5a interactions with Gln127, Leu133, Tyr324, Arg328, Ala335, Tyr799, Tyr802, Leu809, Cys813, Trp899, and Glu900. An H-bond (–OH(Tyr802) → O2(5a)) has been mentioned by a green dotted line. (e & f) enzyme-5b complex interactions, in the active site of the enzyme consisting of Gln127, Leu133, Tyr324, Arg328, Ala335, Tyr799, Tyr802, Leu809, Cys813, Trp899 and Glu900 with H-bond (–OH(Tyr802) → O2(5b)). [In c & f, the colour black, blue, and red represent carbon, nitrogen, and oxygen atom, respectively].

Furthermore, 5b forms an additional H-bond with Glu⁹⁰⁰ (>3.50 Å, Fig. 7e). It is important to mention that gastric H⁺, K⁺ ATPase controls the stomach's acidity by exchanging H⁺ and K⁺ across the epithelial cells of the stomach (Ganser and Forte, 1973; Wallmark et al., 1985). The irreversible inhibitors such as omeprazole antagonize gastric H⁺, K⁺ ATPase by covalent interactions with a conserved cysteine residue (Cys⁸¹³) (Besancon et al., 1997). In contrast, reversible inhibitors such as 2-Methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile (SCH28080) inhibits gastric H⁺, K⁺ ATPase activity in a K⁺ competitive manner in noncovalent interactions (Wallmark et al., 1987). The crystal structure of SCH28080-bound gastric H⁺, K⁺, ATPase showed that the binding site for SCH28080 is located in the luminal cavity of gastric H⁺, K⁺ ATPase (Abe et al., 2011), where it shows a strong affinity for Phe³³², Ala³³⁵, Tyr⁷⁹⁹, Leu⁸⁰⁹, and Cys⁸¹³ (Vagin et al., 2002; Asano et al., 2004; Munson et al., 2005 ).

The peptoids, 5(a-b), strongly interacted with the aminotransferase Aro8 enzyme from Candida albicans (PDB ID: 6HNB) with the binding energies of −10.37 and −9.92 kcal/mol and dissociation constants of 25.09 and 53.16 nM, respectively (Fig. 8).

Aminotransferase Aro8-5(a-b) complex (a, d) enzyme electrostatic surface (b & c) enzyme-5a interactions where Leu28, Lys29, Phe32, Tyr35, Phe42, Gly46, Leu47, Tyr105, Gly106, Thr108, and Glu326 forms enzyme binding site (e & f) enzyme-5b complex where the active site consists of Leu28, Lys29, Phe32, Tyr35, Phe42, Gly46, Leu47, Tyr105, Gly106, Thr108, and Glu326. [In c & f, the colour black, blue, and red represent carbon, nitrogen, and oxygen atom, respectively].

Both ligands show interaction with the same binding pocket consisting of Leu²⁸, Lys²⁹, Phe³², Tyr³⁵, Phe⁴², Gly⁴⁶, Leu⁴⁷, Tyr¹⁰⁵, Gly¹⁰⁶, Thr¹⁰⁸_, and Glu³²⁶ (Fig. 8c & f). The aminotransferase Aro8 is an important target for inhibiting the growth of C. albicans, where it is involved in the decomposition and biosynthesis of positive (Lys, His) and aromatic amino acids (Tys, Phe) (Rząd and Gabriel, 2015; Rząd et al., 2018). Therefore, it can be proposed that both peptoids, 5(a-b), may have promising antifungal activities.

The MD simulations explain the binding stability and dynamics of the peptoid-aminotransferase complexes. The system equilibration was assessed by the potential energy of native and ligand-bound aminotransferase, Aro8, where free aminotransferase Aro shows the average potential energy of 2002703.71 kJ/mol. However, for aminotransferase Aro8-5a-b complexes, slightly lower average potential energies (-1928616.88 and −1928944.74 kJ/mol) show the formation of stable protein–ligand complexes (Fig. 9a).

MD simulation of Aminotransferase Aro-5(a-b) complex, (a) potential energy plot, (b) Radius of gyration (Rg), (c) RMSF plot, (d) RMSD plot.

The stability of the protein–ligand complex is assessed by analyzing the radius of gyration (R_g). R_g corresponds to the total volume of the protein and its high value with higher flexibility protein complex. The average R_g for native aminotransferase Aro was 25.12 Å, while for 5a and 5b complex, the average Rg was 25.39 and 25.30 Å, respectively. According to the R_g plot, it can be observed that the R_g values for aminotransferase Aro-5(a-b) complex were increased after 6 ns of simulation, while the highest values were observed after 17 ns simulation that shows higher flexibility of ligand–protein complex compared to native protein (Fig. 9b). RMSF (root mean square fluctuation) plot shows residual fluctuations in the aminotransferase Aro-5(a-b) complex (Fig. 9c). Significant changes in RMSF from Arg²³ to Ser⁴⁹ and Asp⁹⁵ to Phe¹⁰⁹ confirm the ligand–protein interaction in these regions. Increased fluctuations for 5a were observed at Lys²⁶⁷, Val³²⁷, Tyr³⁶³, His³⁶⁵, Lys³⁶⁶, Trp⁴³⁶, Asn⁴⁴⁹, Ala⁴⁶⁸, Lys⁴⁸³, and Arg⁴⁸⁶, and for 5b, it was observed at Pro⁵⁴, Phe⁵⁵, Pro⁹⁴, Asp⁹⁵, Thr¹⁰⁸, Phe¹⁰⁹, Lys²⁵⁹, Lys²⁶¹, Lys²⁶⁷, and Gln⁴⁷³. RMSD (root mean square deviation) plot also agrees with ligand–protein interactions in the proposed active site (Fig. 9d). Overall, the decrease from Ser²⁶ to Phe⁵³ and Ala⁸⁹ to Asn¹³² in the RMSD plot of 59(a-b) (Fig. 8d).

5(a-b) shows strong hydrophobic binding interactions against another C. albicans enzyme, CYP51 (lanosterol 14α-demethylases) (PDB ID: 5V5Z), with the binding energies of −10.02 and −10.54 kcal/mol and dissociation constant of 45.36 and 18.8 nM, respectively (Fig. 10). The binding site consisted of the amino acids including, Phe⁵⁸, Ala⁶¹, Tyr⁶⁴, Gly⁶⁵, Pro⁶⁸, Leu⁸⁷, Leu⁸⁸, Tyr¹¹⁸, Pro²³⁰, Phe²³³, His³⁷⁷, Ser³⁷⁸, Phe³⁸⁰, Tyr⁵⁰⁵, Ser⁵⁰⁶, and Ser⁵⁰⁷ (Fig. 10c). Lanosterol 14α-demethylases is a key enzyme in fungi that catalyzes ergosterol biosynthesis (Lepesheva et al., 2008). Azole-based drugs exert potential antifungal activity in humans by inhibiting this enzyme (Vanden Bossche et al., 1986).

CYP51-5a-b complex (a, d) Electrostatic surface for the ligand-enzyme complex. (b & c) 5a-enzyme interactions, where the binding site of the enzyme consists of Phe58, Ala61, Tyr64, Gly65, Pro68, Leu87, Leu88, Tyr118, Pro230, Phe233, His377, Ser378, Phe380, Tyr505, Ser506, and Ser507 (e & f) 5b-enzyme complex interactions, where the active site of the enzyme consists of Phe58, Ala61, Tyr64, Gly65, Pro68, Leu87, Leu88, Tyr118, Pro230, Phe233, His377, Ser378, Phe380, Tyr505, Ser506, and Ser507. [In penal e & f, the colour black, blue, and red represent carbon, nitrogen, and oxygen atom, respectively].

MD simulations for native CYP51 and its complex with 5(a-b) confirm the ligand–protein docking. The average potential energy for native CYP51 was calculated to be −1284000.05 kJ/mol, whereas, for CYP51-5a and CYP51-5b, it was estimated to be −1285481.58 and −1288042.691 kJ/mol, respectively. Therefore, in terms of energy, it can be suggested that CYP51-5(a-b) complex is slightly more stable than the native CYP51 enzyme (Fig. 11a). The average R_g for native CYP51 was found to be 23.97 Å, while for CYP51-5a and CYP51-5b complex, it was found to be 24.15 and 24.09 Å, respectively, showing 5(a-b)- CYP51 interactions may lead to an open form of the enzyme and may not perform native functions (Fig. 11b). No significant change was observed in RMSF for CYP51-5(a-b) complexes and native CYP51 protein (Fig. 11c). Minor fluctuations were observed in the RSMD for bound and free enzyme (Fig. 11d). For 5a complex, some minor fluctuations were observed for Pro⁵⁶-Tyr⁶⁴, Ser¹³⁷-Glu¹⁴¹, and Ser²⁸⁴-Met²⁹², and for 5b complex, fluctuations were observed for Leu⁵⁰-Pro⁵⁶, Met⁸⁶-Met⁹², Phe¹⁰⁵-Asp¹¹¹, Glu²⁰⁸, Met²⁰⁹, Pro²³⁰, Trp²⁴⁴-Arg²⁶⁴, Thr³⁸⁴-Leu⁴⁰³, and Lys⁴⁹⁹-Ser⁵⁰⁷. These RMSD changes indicate the ligand–protein interactions in the binding site of the enzyme.

MD simulations for CYP51-(5a-b) complex. (a) potential energy plot, (b) Radius of gyration (Rg), (c) RMSF plot, (d) RMSD plot.

Strong interactions were observed between peptoids 5(a-b) and human acetylcholinesterase (AChE) (PDB ID: 4MOE), where binding energy was found to be −10.24 kcal/mol and dissociation constant 31.08 nM (Fig. 11). The binding site consists of amino acids, including Leu⁷⁶, His²⁸⁷, Trp²⁸⁶, Glu²⁹², Phe³³⁸, and Tyr³⁴¹. A hydrogen bond (3.17 Å) between O2 of 5a and the hydroxyl group of Tyr⁷² was also observed (Fig. 12c), while 5b complex showed only hydrophobic interactions with a binding energy of −9.85 kcal/mol and dissociation constant of 60.34 nM. The binding site consists of Tyr⁷², Asp⁷⁴, Thr⁷⁵, Leu⁷⁶, Trp²⁸⁶, Glu²⁹², Ser²⁹³, Val²⁹⁴, Phe²⁹⁵, Phe²⁹⁷, Tyr³³⁷, Phe³³⁸, and Tyr³⁴¹ amino acids (Fig. 12f). However, 5b strongly interacted with amino acids (Tyr⁷², Asp⁷⁴, Trp²⁸⁶, and Tyr³⁴¹) of the peripheral active site (PAS) of AChE (Gondal et al., 2023). Thus, it was predicted that 5b is a better inhibitor as compared to 5a.

AChE-5(a-b) complex (a, d) Enzyme electrostatic surface, (b & c) 5a interactions with Leu76, His287, Trp286, Glu292, and Phe338, while Tyr341 forms an H-bond (OH(Tyr72) → O2(5a)) (e & f) enzyme-5b complex involve amino acids including Tyr72, Asp74, Thr75, Leu76, Trp286, Glu292, Ser293, Val294, Phe295, Phe297, Tyr337, Phe338, and Tyr341. [In penal e & f, the colour black, blue, and red represent carbon, nitrogen, and oxygen atom, respectively].

Acetylcholinesterase (AChE) is involved hydrolysis of acetylcholine (Rosenberry, 1979) and plays an important role in Alzheimer's disease (Giacobini, 2000). Reversible and irreversible inhibitors can block the AChE activity to mask Alzheimer's disease. The irreversible inhibitors block AChE by covalently bonding to Ser²⁰³ (Millard and Broomfield, 1995). The interaction of natural product inhibitor, Territrem B (TB), with amino acids including Trp⁸⁶, Tyr⁷², Gly¹²¹, Tyr¹²⁴, Ser¹²⁵, Ser²⁰³, Trp²⁸⁶, Ser²⁹³, Phe²⁹⁵, Phe²⁹⁷, Glu³³⁴, Tyr³³⁷, Phe³³⁸, Tyr³⁴¹, and His⁴⁴⁷ was reported at the active site of AChE (PDB ID: 4M0F) (Cheung et al., 2013). A good correlation was found between 5(a-b) complex with AChE and reported docking.

The average potential energy for native AChE was −1258875.20 kJ/mol, whereas 5a-AChE and 5b-AChE showed −1296821.58–1298848.165 kJ/mol, respectively (Fig. 13a). The average R_g for free AChE was 23.28 Å, while for 5a-AChE and 5b-AChE, it was found to be 23.21 and 23.25 Å. The R_g plot showed that the R_g value for the 5(a-b) complex was lower than the free enzyme. Therefore, it was assumed that AChE forms a stable complex with 5(a-b) (Fig. 13b). The RMSF fluctuations for the AChE-5a complex were observed for Arg¹³, Lys²³, Tyr⁷⁷-Asn⁸⁹, Val¹³²-Gln¹⁴⁰, Val²³⁹, Arg²⁴⁶, Thr²⁶⁷-Leu²⁶⁹, His²⁸⁴, Val²⁸⁸, Leu³⁵³-Glu³⁵⁸, Val³⁷⁰, Leu³⁹⁸, Asp⁴⁰⁰, Val⁴¹⁰, Leu⁴⁴¹-Glu⁴⁶⁹, Trp⁵⁰⁰, Leu⁵⁴⁰, and Ala⁵⁴². 5b fluctuations were observed at Thr⁷⁵-Glu⁸⁴, Leu¹⁹⁹, Phe²⁰⁰, Gln²⁵⁰, Gln²⁹¹-Phe²⁹⁷, Ala³⁶¹, Gln³⁶⁹, Pro⁴⁴⁶, and Arg⁵³⁴-Pro⁵³⁷. In case of RMSD, for 5a, fluctuations were observed for Phe⁸⁰-Pro⁸⁸, Glu²⁶⁸, Val³²⁸, Leu⁴⁴¹-Ile⁴⁵⁴, and Tyr⁴⁶⁵-Met⁴⁷⁷. For 5b, fluctuations were observed for Arg²⁴⁶-Arg²⁹⁶, Leu³⁶⁰-Val³⁶³, and Pro³⁹¹-Arg³⁹⁵ (Fig. 13c). The RMSD fluctuations confirm the ligand–protein interactions at the binding site (Fig. 13d).

MD simulation of AChE-peptoid (5a-b) complex, (a) potential energy plot, (b) Radius of gyration (Rg), (c) RMSF plot, (d) RMSD plot.

ADME analyses showed that peptoids 5(a-b), are non-toxic. The comparison of ADME properties shows that 5b has a smaller logS (-6.92) than 5a (-7.12), showing 5a has slightly poor membrane permeation than 5b. The 5(a-b) were also predicted to be inhibitors of P-gp (P-glycoprotein 1) and CYP2D6 (cytochrome P450 2D6) (Table S5).

3.2.1

3.2.1 Umbrella sampling of 5(a-b)-AChE complex

The umbrella sampling simulations were performed to measure the interaction strength between AChE and peptoids 5(a-b). WHAM results show that the AChE-5(a) complex is strongly bound as the separation requires an energy barrier of 12 kcal/mol from their stable binding position (Fig. 13A), while AChE-5(a) complex shows two stable binding positions at the energy barriers of 18 and 24 kcal/mol (Fig. 14).

Umbrella sampling of AChE-peptoid(5a-b) complex, (A) Peptoid 5a (B) Peptoid 5b.

4 Conclusion

The quinoline-based peptoids 5(a-b) were synthesized via Ugi 4-CR to introduce the quinoline ring in the peptoid backbone to assess their biological activities. Both peptoids were structurally characterized using spectroscopic techniques (FT-IR, NMR, and ESI-MS). The experimental FT-IR values were compared with computational spectral values, and good agreement was found. NBO analysis of 5(a-b) was performed to predict electronic transitions in the orbitals. The HOMO-LUMO energy gaps, 4.45 and 4.37 eV were predicted for 5a and 5b, respectively. The global reactivity parameters were calculated using the FMOs energies. The low energy gap of 5b suggested strong charge-transfer capabilities and more significant NLO properties. The average polarizabilities <α> values of 5(a-b) were 397.54 and 375.11 a.u. The second-order polarizability (β_tot) values of 5(a-b), 394.15, and 381.31 a.u were significant enough to give NLO response. According to DFT analysis, 5b was predicted to be more reactive comparatively. Therefore, it can act as a better ligand in the biological system. The in-silico study (molecular docking and simulations) was conducted to evaluate its reactivity at the molecular level. The molecular docking studies show that 5(a-b) can inhibit gastric H⁺, K⁺ ATPase with favourable interactions with key residues. 5(a-b) also showed high binding energy against C. albicans enzymes which show the antifungal potential of 5(a-b) peptoids. However, the in-vitro activity of 5(a-b) was tested against AChE to evaluate its efficacy against Alzheimer's disease. The molecular interactions were explained by molecular docking, which showed key interactions against amino acids of the active site of AChE. Furthermore, docking analysis was verified by molecular dynamic simulations and umbrella sampling.

CRediT authorship contribution statement

Shahzaib Akhter: Formal analysis, Investigation, Methodology, Software, Visualization. Odette Concepcion: Formal analysis, Investigation, Methodology, Validation, Visualization, Writing – original draft, Writing – review & editing. Alexander Fernández de la Torre: Formal analysis, Methodology, Visualization. Akbar Ali: Formal analysis, Investigation, Project administration, Resources, Supervision, Writing – original draft, Writing – review & editing. Abdul Rauf Raza: Funding acquisition, Investigation, Project administration, Supervision, Writing – original draft, Writing – review & editing. Rida Eman: Software, Validation. Muhammad Khalid: Investigation, Software, Validation. Muhammad Fayyaz ur Rehman: Project administration, Software, Writing – original draft, Writing – review & editing. Muhammad Safwan Akram: Methodology. Hayssam M. Ali: Investigation, Validation, Writing – review & editing.

Acknowledgements

We are very thankful to Pedro J. Silva (Universidade Fernando Pessoa, Porto, Portugal) for providing WHAM-YASARA scripts for umbrella sampling as well as guiding through the computational analysis.

Funding

The authors would like to extend their sincere appreciation to the Researchers Supporting Project number (RSP2023R123), King Saud University, Riyadh, Saudi Arabia.We are also very thankful to Pedro J. Silva (Universidade Fernando Pessoa, Porto, Portugal) for providing WHAM-YASARA scripts for umbrella sampling as well as guiding us through the computational analysis. Funding This work was funded by the Researchers Supporting Project number (RSP2023R123), King Saud University, Riyadh, Saudi Arabia.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Appendix A

Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.arabjc.2023.104570.

Appendix A

Supplementary material

The following are the Supplementary data to this article:

Supplementary data 1

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Introduction

Experimental

General experimental
Computational procedures
The In-silico studies

Results and discussion

DFT study
The In-silico studies

Conclusion

CRediT authorship contribution statement

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Synthesis, spectroscopic characterization, DFT and molecular dynamics of quinoline-based peptoids

Abstract

Keywords

Peptoids

Ugi-4CR

Molecular dynamic

WHAM

Umbrella sampling

anti-cholinesterase

1 Introduction

2 Experimental

2.1 General experimental

2.1.1 General procedure for the synthesis of N-benzyl-N-[(2́-(cyclohexylamino)-1́-{(1́́S, 5́́R)-6́́,6́́-dimethylbicyclo[3.1.1]hept-2́́-en-2́́-yl}-2́-oxoethyl)]quinoline-2-carboxamide (5a)

2.1.2 General procedure for the Synthesis of N-benzyl-N-[(2́-(cyclohexylamino)-1́-{(1Ś́,5́́R)-6́́,6́́-dimethylbicyclo[3.1.1]hept-2́́-en-2́́-yl)}-2́-oxoethyl)]quinoline-6-carboxamide (5b)

2.2 Computational procedures

2.2.1 DFT calculations

2.3 The In-silico studies

2.3.1 Umbrella sampling of 5(a-b)-AchE complex

3 Results and discussion

3.1 DFT study

3.1.1 Vibrational analysis

3.1.1.1 C—H vibrations

3.1.1.2 C⚌C stretching vibration

3.1.1.3 C—C stretching vibration

3.1.1.4 C⚌O vibration

3.1.1.5 N—H vibrations

3.1.1.6 C—N vibrations

3.1.2 UV–visible analysis

3.1.3 Natural bond orbital (NBO) analysis

3.1.4 Natural population analysis (NPA)

3.1.5 Molecular electrostatic potential (MEP) analysis

3.1.6 Frontier molecular orbital (FMO) analysis

3.1.7 Nonlinear optical (NLO) properties

3.2 The In-silico studies

3.2.1 Umbrella sampling of 5(a-b)-AChE complex

4 Conclusion

CRediT authorship contribution statement

Acknowledgements

Declaration of Competing Interest

References

Appendix A

Supplementary material

Appendix A

Supplementary material

Supplementary data 1

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