Journal of Computational Biophysics and Chemistry

Tea is a very important source of the terepenoid $\alpha$-ionone, which is much appreciated as a medicinal beverage. Schiff bases are a very important class of organic compounds usually formed by the condensation of carbonyl compounds with amines. $\alpha$-ionone is a carbonyl terpenoid obtained from Schiff bases on condensation with nucleobases like adenine and cytosine and the amino acid $l$-leucine. We synthesized these three Schiff bases and characterized them using UV, FTIR, and H1 and C13-NMR spectra. The molecules were optimized using B3LYP/6-311+G(2d,p) level followed by the simulation of FT-IR spectra, of which the simulated and experimental spectra showed complete agreement. The UV spectra were simulated using TD-DFT, and the electronic excitations were carefully analyzed. Natural bond orbitals provided an analysis of the stability of the compound, which is supplemented by the data from frontier molecular orbital analysis. Detailed wavefunction analysis is reported which predicts the active centers, reactivity profile, and the extent of non-covalent interactions. PASS indicated that compounds show antieczemic properties and antiarthritic properties, which is confirmed with the help of molecular docking results.

Glycoprotein VI (GPVI) plays an important role in platelet aggregation, and inhibition of GPVI may block thrombosis with a low bleeding risk, thus making GPVI a promising antithrombotic target. In this paper, the binding mode of losartan, a known GPVI inhibitor, was investigated using molecular docking and molecular dynamics methods as well. Docking results can determine the location site of the phenyl tetrazole group of losartan, but the direction of the two substitute groups on imidazole ring is uncertain. Therefore, two sample conformations were selected, and long-time molecular dynamics simulations were carried out. The rotatable bond of C–N connecting the imidazole ring and the middle benzene ring was monitored during the simulation. The results showed that this dihedral angle is mostly distributed at about $-120^{\circ }$ for both systems, implying that this conformation is the dominant conformation. The switchable conformation may be the reason for low activity of losartan to GPVI. Losartan1 system was well equilibrated and selected as the receptor to perform drug repurposing screening, and several drugs with a similar binding mode as losartan were identified. Our study may enhance the mechanism understanding of GPVI receptor, giving insights into the design and discovery of novel GPVI inhibitors.

The computationally hard protein–protein complex structure prediction problem is continuously fascinating to the scientific community due to its biological impact. The field has witnessed the application of geometric algorithms, randomized algorithms, and evolutionary algorithms to name a few. These techniques improve either the searching or scoring phase. An effective searching strategy does not generate a large conformation space that perhaps demands computational power. Another determining factor is the parameter chosen for score calculation. The proposed method is an attempt to curtail the conformations by limiting the search procedure to probable regions. In this method, partial derivatives are calculated on the coarse-grained representation of the surface residues to identify the optimal points on the protein surface. Contrary to the existing geometric-based algorithms that align the convex and concave regions of both proteins, this method aligns the concave regions of the receptor with convex regions of the ligand only and thus reduces the size of conformation space. The method’s performance is evaluated using the 55 newly added targets in Protein–Protein Docking Benchmark v 5 and is found to be successful for around 47% of the targets.

A new Schiff base compound and its derivative, 3-cyclopropyl-4-(4-nitrofuran-1-yl)methyleneamino-4,5-dihydro-1$H$-1,2,4-triazol-5-one (3-CNM) and 1-acetly-3-cyclopropyl-4-(4-nitrofuran-1-yl)methyleneamino-4,5-dihydro-1$H$-1,2,4-triazol-5-one (1-ACNM), were synthesized. The structures of compounds were characterized by ${}^{13}$C-NMR, ¹H-NMR and FT-IR spectroscopy techniques. The antioxidant capacities of the molecules were investigated by different methods (metal chelation, DPPH and reducing power). Some quantum chemical calculations are performed on the B3LYP, B3PW91, MPW1PW91 functionals with the 6-311++G(d,p) level basis set of the density functional theory (DFT). Using the optimized structures of Schiff bases, the frontier molecular orbital, the theoretical spectroscopic and the nonlinear optic (NLO) analysis, the molecular electrostatic potential (MEP) surface, the thermodynamic parameters, the dipole moment, the molecular geometric properties and the total energy were calculated. The calculation results showed that the 3-CNM compound can be used as a suitable and good nonlinear optical compound. In addition, electronegative and electropositive atoms were determined from the MEP surface map. The difference between ($\mathrm{\Delta }E$) the highest occupied molecular orbitals (HOMO) and the lowest unoccupied molecular orbitals (LUMO) energies was calculated as 3.3eV and 3.4eV for 3-CNM and 1-ACNM, respectively, and these values express the chemical stability of the molecule and the orbital interactions. This work is important because it includes the synthesis of two new molecules and theoretical calculations that support their experimental properties. It can also provide significant benefits in terms of synthesis of similar Schiff base compounds and their calculated electronic, geometric and thermodynamic properties.

Drug discovery is still behind in the race compared to vaccine discovery in fighting COVID-19. In this study, we have selected 41 quinazoline alkaloids from two natural product databases to create an adequate library and performed detailed computational studies against the main protease ($M^{\mathrm{\text{pro}}}$) of SARS-CoV-2 using two reference compounds, namely famotidine and X77. The screening of the library was carried out by blending the rigid docking and pharmacokinetic analysis that resulted in nine alkaloids as initial leads against $M^{\mathrm{\text{pro}}}$. These initial leads were further subjected to advanced flexible docking and were compared with reference compounds (famotidine and X77) for the analysis of structure-based interactions. For further selection, a second screening was carried out based on binding energies and interaction profiles that yielded three alkaloids, namely CNP0416047, 3-hydroxy anisotine and anisotine as final leads. The stereo-electronic features of lead alkaloids were further investigated through additional E-pharmacophore mapping against crystallized X77 reference compound. Additionally, the reactivity of lead alkaloids at the binding sites of the protein was estimated by measuring the electron distribution on the frontier molecular orbitals and HOMO–LUMO band energies. Finally, the stabilities of complexes between lead alkaloids with the protein were accessed extensively using robust molecular dynamics simulation through RMSD, RMSF, Rg and MM-PBSA calculation. Thus, this study identifies three natural quinazoline alkaloids as potential lead inhibitors of $M^{\mathrm{\text{pro}}}$ through extensive computational analysis.

Human African trypanosomiasis (HAT), a fatal infection caused by Trypanosoma brucei (T. brucei) is considered as a neglected disease in the tropical areas, and newer agents with unique mechanism of action are urgently needed. In this work, 65 Imidazopyridine analogues from known literature were selected for building statistically robust genetic algorithm (GA) based QSAR models. Furthermore, values for the various cross-validation properties supported its statistical robustness (model 1, $R_{\mathrm{\text{tr}}}^2=0.8537$, RMSE${}_{\mathrm{\text{cv}}}=0.3586$, MAE${}_{\mathrm{\text{cv}}}=0.2642$, CCC${}_{\mathrm{\text{cv}}}=0.8953$, and $Q_{\mathrm{\text{LMO}}}^2=0.7887$). Our in silico ADMET analysis revealed that a designed molecule, S10 may act as potent lead (T. brucei, pEC${}_{50}$ ($\mu$M), $\mathrm{\text{predicted}}=8.200$) with better pharmacokinetics, no carcinogenicity, class III acute oral toxicity, minimal OCT1 and OCT2 inhibitions and no eye corrosion profiles. Our molecular docking analysis (on 42 drug targets) for a dataset and designed molecules demonstrated higher binding affinity of Imidazopyridine analogues with T. brucei farnesyl diphosphate synthase (TbFPPS) (PDB id: 2I19). This observation was further supported by 100ns molecular dynamics analysis retaining better stability of complex. Thus, imidazopyridine analogues would provide a promising scaffold for the development of anti-HAT agents.

This study was done to report virtual screening and molecular docking studies of sulfacetamide derivatives as new antimicrobial drugs, belonging to the pharmacological class of sulfonamides. For this purpose, sulfonamide functional groups from a library of chemical structures were converted into acetylenic sulfone and acetylenic sulfonamide functional groups to introduce a new class of antimicrobial drugs with mechanisms of action of dihydropteroate synthase inhibitors (DHPS). Initially, a library of compounds containing approximately 170 acetylenic sulfone ligands was created by similarity search method, and a library containing 170 acetylenic sulfonamide ligands was designed to be administered as new inhibitors. After designing, their molecular docking energies were calculated by three software programs including Arguslab4.0.1, AutoDock Vina and Molegro Virtual Docker and the results were compared in terms of binding energy. Although acetylenic sulfonamide compounds showed better results, acceptable results were observed in both groups of compounds. Adsorption, distribution, metabolism and excretion (ADME) properties of acetylenic sulfones/acetylenic sulfonamide analogs were also analyzed using the admetSAR program. These new derivatives can be used in drug improvement processes for the treatment of antibacterial infections after performing further studies.

The COVID-19 has raised a public health catastrophe in early 2020 worldwide. Despite several approved vaccines that have repressed the pandemic and decreased the mortality rate since then, attempts to discover an effective antiviral drug have not indicated reliable results. In this research, in silico studies (virtual screening and molecular docking) were performed based on quinoline structure to identify novel drug candidates against SARS-CoV-2 before laboratory evaluations. A chemical library consisting of 548 compounds was collected from literature mining of five databases to select the best ligands interacting with three target proteins of SARS-CoV-2, including the main protease, spike protein, and chimeric receptor-binding domain in a complex of human angiotensin-converting enzyme 2. The top five compounds that presented suitable binding energy against each target protein are reported in detail for the first time. Notably, new compound N-4-(6-methyl-3-pyridinyl) phenyl)-9-acridinamine showed high affinity to all selected proteins. These identified compounds will help in speeding up the drug development against COVID-19.