Journal of Computational Biophysics and Chemistry

In a continuing effort for our research group, we identify new active 1,2,4-triazine derivatives as novel cancer preventive agents that target CYP1A1 activity, through the application of quantitative structure–activity relationship (QSAR) theory. For this purpose, novel fused 1,2,4-triazine derivatives, namely, 4-Amino-6-substituted benzyl-3-(2-substituted benzylidenehydrazinyl)-1,2,4-triazin-5(4H)-ones and acetylated 6-substituted benzyl-7-oxo-3-substituted phenyl-2,3-dihydro-7$H$-[1,2,4]triazolo[4,3-$b$][1,2,4]triazine analogs were utilized for the prediction of the QSAR model. Furthermore, the application of this QSAR equation served successfully as a rational guide for predicting the activities of newly synthesized analogs. The DFT calculation was applied to recognize the physicochemical parameters at B3LYP/6- 311G^* level to gain a clear view of global and local molecular reactivity. Besides, the molecular features of the investigated compounds were identified through HOMO, LUMO and molecular electrostatic potential (MEP) which were plotted to determine the charge transfer within the molecules. Promising two novel 1,2,4-triazine compounds were identified with observed significant inhibitions (83% and 67%) and CYP1A1 activity was predicted. The chemical configuration of the two actives showed good alignment of $p$-methoxy benzyl aminotriazinone fragments, hydrazino and carbonyl linker in structure–activity relationship and interaction. Molecular modeling analysis supported with MD simulations was undertaken to investigate different binding interactions with the target binding site. These projects offered a good application of a promising QSAR model for prediction of highly active compounds for further lead optimization.

The atomically precise method has become an important technique for adjusting the core of thiolate-protected gold nanoclusters to improve biological, physical, and chemical properties. But, the doping effect on the structural stability across different elements has not been modeled within the scope of a bigger picture. Therefore, in this work, the H₂S–nanoalloy complexes with different doping metal atoms have been investigated to elucidate the effects of the dopant on the structures. Indicated by simplified model complexes and density functional theory (DFT) simulation results, the zinc group atoms as dopants may be influenced by surrounded gold atoms, and binding to the thiolate units is enhanced by the addition of gold atoms. The reactivity of the zinc group atoms may be activated by a gold nanocluster. The simulated zinc group data when combined with the gold group and platinum group data can be summarized in the perspective of balance between the ligand–core binding and core cohesive energies. Most dopants move the modeled nanoclusters away from the balance, especially when the metal atom replaced the gold atom in gold–sulfur bindings. Besides, when cores of the nanoclusters are dominated by gold atoms, the dopants may achieve “saturation” such that the balance in the doped clusters may be corrected. This work provides a simple profile to understand the internal shift of the structure introduced by the atomically precise method.

Angiotension-converting enzyme 2 (ACE2) is the host receptor of the serious-acute respiratory syndrome coronavirus 2 (Sars-CoV-2) spike protein. In this article, the interaction of ACE2 with the receptor binding domains (RBD) of Wuhan-Hu-1 and United Kingdom (UK) and South African (SA) variants is examined in silico. Their Gibbs free energies were computed using a protein binding energies prediction model. The interaction characteristics of RBDs with possible inhibitory compounds as well as a standard drug, Paxlovid, were also investigated, and Gibbs free energies were computed. Molecular modeling, molecular dynamics and molecular docking methods were employed and the results are compared and discussed.

The HA3 influenza (H3N2) influenza was originally found in 2011 and later appeared in January 2021. As per WHO report, H3N2 has the potential of causing a pandemic; therefore, an inhibitor for H3N2 should be designed. The hemagglutinin variants have typical 18 subtypes present in humans. Therefore, in the study, we generated the phylogenetic tree for understanding the similarity sequence between 18 subtypes and also the sequence of similarity was compared to H3N2. Thereafter, scaffold structures of FDA-approved Peramivir were generated, among which, four compounds were selected based on their drug-likeness and synthetic feasibility for performing docking and MD simulations. Theoretical evaluations, such as electronic, spectroscopic, binding energy, Root Mean Square Deviation (RMSD), Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET), were performed to validate the derived chemical structures and identify their potential of acting as drug compounds. In the present work, derivatives of 2-methyl tetrahydrofuran-$n$-carboxylic acids show the inhibitory activity with H3N2 (PDB ID: 4WEA) with stable conformations.

The aim of this in silico study was the identification of NSAID’s amides with ability to bypass the COX inhibition and selectively target mPGES-2 and FLAP. Molecular binding analysis was conducted on selected compounds using molecular docking, MD simulations and MM/GBSA calculations to assess their potential in the prevention of neuroinflammation. Ligand-based virtual screening was performed in the ChEMBL database, thereby 196 compounds were obtained. Resulting compounds were passed through the BBB permeability and druglikeness filters, and six compounds were selected for further analysis. Molecular docking analysis showed that compounds 4 and 6 can avoid the COX inhibition and simultaneously target mPGES-2 and FLAP. These two top docked compounds were subjected to MD simulations, which indicated that complexes of compound 4 with mPGES-2 and FLAP have shown conformational stability throughout the simulation. Calculated MM/GBSA binding energies confirmed that compound 4 demonstrated dual binding affinity against mPGES-2 and FLAP. Based on the docking score, MM/GBSA average binding energy and MD results, compound 4 emerged as the best in silico hit for the prevention of neuroinflammation.

In this study, a set of 72 styryl lactone compounds reported from Goniothalamus species were docked against envelope ($E$), NS2B/NS3, NS5 methyltransferase (MTase), and NS5 RdRp dengue virus (DENV) protein. As a result, compounds 5, 37, 38, and 47 were identified as potential dengue protease inhibitors based on minimal docking energy values and multiple interactions with binding sites. The results from in-silico Lipinski’s rule and ADMET analysis showed that these compounds were predicted to fulfil the drug-likeness properties. These ligands were found to fit in well and remain stable in the binding site of the envelope protein, NS2B/NS3, NS5 MTase, and NS5 RdRp. The results from molecular dynamic (MD) simulations indicate that the ligand–protein complex of compound 37 with NS5 MTase was stable throughout the MDs simulations and could interact with essential amino acids within the active sites.

Nonequilibrium Green’s function formalism is used to set the chemiresistor device for analyzing the sensing ability of pristine and metal-doped (Al, Fe and Mn) armchair graphene nanoribbons (AGNRs) for the detection of hydrogen halide gases — HF, HCl and HBr. Metal doping is found to enhance the adsorptive strength and sensing ability of the ribbon. On Al-AGNR, all three halide gases follow dissociative chemisorption while on Fe-AGNR and Mn-AGNR, these gases adsorb nondissociatively. The computed current–voltage characteristics indicate selective response of Mn-AGNR toward HF and of Fe-AGNR toward HBr. The origin of this selectivity has been discussed in terms of difference in the density-of-state profiles of the studied AGNR systems.

Hydrazones typically have an azomethine ‘–NHN=CH group’ which is crucial for varieties of pharmacological activities. In this study, we have synthesized a set of 15 new hydrazones (5A–5O) of 2-((2,3-dihydro-1H-inden-4-yl)oxy)acetohydrazide, which were characterized with various spectroscopic methods. It was found that the compound 5H had significant bioactivities (Antioxidant: DPPH assay: 80.3% inhibition; at 100$\mu$g/mL concentration; Antibacterial: Minimum inhibitory concentration (MIC) of 6.25$\mu$g/mL against E. coli; Antimycobacterial, H37Rv Vaccine strain: MIC of 3.12$\mu$g/mL; Anticancer: Trypan Blue assay, MCF-7; IC${}_{50}$ values of 84.3mM). To understand the probable underlying antibacterial mechanisms, we examined all hydrazones against a common bacterial target (2,2-dialkylglycine decarboxylase, PDB ID: 1d7u) and pantothenate synthase from Mycobacteria (PDB ID: 3ivx) using molecular docking. Our molecular dynamics simulations for 100ns for both the complexes (5H:1d7u and 5H:3ivx) revealed significant stability of ligand–protein complex. Moreover, to correlate structural features with biological activity, we have developed statistically significant 5-parametric Quantitative Structure–Activity Relationships (QSAR) models. The pharmacophore hypothesis, AADHR_1 (5-point) signifies its importance for biological activities. Finally, we have examined the theoretical and pharmacokinetics and toxicity properties of all synthesized compounds.