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Abstract With the rapid rate of SARS-CoV-2 Main protease (Mpro) structures deposition, a computational method that can combine all the useful structural features becomes crucial. This research focuses on the frequently occurring atoms and residues to find a generalized strategy for inhibitor design given a large amount of protein complexes from SARS-CoV in contrast to SARS-CoV-2 Mpro. By superposing large numbers of the ligands onto the protein template and grid box, we can analyse which part of the structure is conserved from position-specific interaction for both data sets for the development of pan-Mpro antiviral design. The difference in conserved recognition sites from the crystal structures can be used to determine specificity determining residues for designing selective drugs. We can display pictures of the imaginary shape of the ligand by unionising all atoms from the ligand. We also pinpoint the most probable atom adjustments to imitate the frequently found densities from the ligand atoms statistics. With molecular docking, Molecular Dynamics simulation, and MM-PBSA methods, a carbonyl replacement at the nitrile warhead (N5) of Paxlovid’s Nirmatrelvir (PF-07321332) was suggested. By gaining insights into the selectivity and promiscuity regions for proteins and ligands, crucial residues are highlighted, and the antiviral design strategies are proposed.

The crystal structure of the natural product zeylenone, C21H18O7, was confirmed by single-crystal X-ray diffraction. The crystal structure has three chiral centers at positions C1, C5 and C6 of the cyclohexanone ring, but the absolute configuration could not be determined reliably. The methyl benzoate and benzoyloxy substituents at positions C1 and C5 of the cyclohexenone ring are on the same side of the ring with the dihedral angle between their mean planes being 16.25 (10)°. These rings are almost perpendicular to the cyclohexenone ring. The benzoate groups and two hydroxyl groups on the cyclohexenone ring form strong hydrogen bonds to consolidate the crystal structure. In addition, weak C—H...O hydrogen bonds also contribute to the packing of the structure.

The rhKU_Sej_LRR_2271 protein is introduced as one of the leptospiral vaccine candidates since it contains the predicted immunogenic epitopes. The in-silico sequence and structural based analysis have been used in this study to analyze MHC class I and class II-restricted epitopes of the protein. Six epitope prediction programs were employed, which the epitopes with high prediction scores from each program were aligned. The 21 of potentially unrestrained epitopes with prediction scores above the cut-off value from at least two prediction programs were selected. The 3D-molecular modeling, docking, and molecular dynamic simulation were performed to evaluate the affinity binding between peptide-MHC complex and T-cell receptor. One promising epitope, which is 171-LLFLPLIKI, showed the potency in binding to both MHC class I and II alleles. Two newly designed peptides containing epitopes which can bind to over 3 of MHC alleles, LL17:171-LLFLPLIKILYVDRNKL-187 and SL19:209-SLNSGIKALPFNYEKLVNL-227, significantly increased interferon-gamma (IFNg)-producing specific T-cell responses in the rhKU_Sej_LRR_2271 immunized rabbits compared to nonimmunized rabbits. The LL17 peptide can also induce interferon-gamma-producing specific CD4+ T-cell responses in the immunized rabbits. For the evaluation of humoral immune responses, the immunized rabbits have a significantly greater amount of specific IgG in plasma than the nonimmunized rabbits. Ex-vivo study of T-cell responses in animal model using flow cytometry confirmed an accomplishment of the theoretically in-silico analysis for discovering potential T-cell epitopes of the protein. The results show that the rhKU_Sej_LRR_2271 protein containing promiscuous T-cell epitopes, which can induce both humoral and cell-mediated immune responses, is a prospective protein candidate for leptospiral vaccine development.

A series of 3-amino-6,7-dimethoxycoumarins conjugated with the N-benzylpyridinium moiety through an amide-bond linkage was synthesized and evaluated for their acetylcholinesterase inhibitory activity. A number of the benzylpyridinium derivatives exhibited potent activities with inhibitory concentration (IC50) values in the nanomolar concentration range. Among them, the 2,3-difluorobenzylpyridinium-containing compound was the most potent inhibitor with an IC50 value of 1.53 ± 0.01 nM. Docking studies revealed that the synthesized compounds inhibit the target enzyme by a dual binding site mechanism whereby the coumarin portion binds with the peripheral anionic site while the N-benzylpyridinium residue binds with the catalytic anionic site of the enzyme.

The enoyl-ACP reductase enzyme (InhA) from M. tuberculosis is recognized as the primary target of isoniazid (INH), a first-line antibiotic for tuberculosis treatment. To identify the specific interactions of INH-NAD adduct and its derivative adducts in InhA binding pocket, molecular docking calculations and quantum chemical calculations were performed on a set of INH derivative adducts. Reliable binding modes of INH derivative adducts in the InhA pocket were established using the Autodock 3.05 program, which shows a good ability to reproduce the X-ray bound conformation with rmsd of less than 1.0 Å. The interaction energies of the INH-NAD adduct and its derivative adducts with individual amino acids in the InhA binding pocket were computed based on quantum chemical calculations at the MP2/6-31G (d) level. The molecular docking and quantum chemical calculation results reveal that hydrogen bond interactions are the main interactions for adduct binding. To clearly delineate the linear relationship between structure and activity of these adducts, CoMFA and CoMSIA models were set up based on molecular docking alignment. The resulting CoMFA and CoMSIA models are in conformity with the best statistical qualities, in which r2cv is 0.67 and 0.74, respectively. Structural requirements of isoniazid derivatives that can be incorporated into the isoniazid framework to improve the activity have been identified through CoMFA and CoMSIA steric and electrostatic contour maps. The integrated results from structure-based, ligand-based design approaches and quantum chemical calculations provide useful structural information facilitating the design of new and more potentially effective antitubercular agents as follow: the R substituents of isoniazid derivatives should contain a large plane and both sides of the plane should contain an electropositive group. Moreover, the steric and electrostatic fields of the 4-pyridyl ring are optimal for greater potency.

Snakebite envenomations cause severe local tissue necrosis and the venom metalloproteinases are thought to be the key toxins involved. In this study, the ethanolic extract from seed kernels of Thai mango (Mangifera indica L. cv. ‘Fahlun’) (Anacardiaceae) and its major phenolic principle (pentagalloylglucopyranose) exhibited potent and dose−dependent inhibitory effects on the caseinolytic and fibrinogenolytic activities of Malayan pit viper and Thai cobra venoms in in vitro tests. molecular docking studies revealed that the binding orientations of the phenolic principles were in the binding pockets of snake venom metalloproteinases (SVMPs). The phenolic principles could form hydrogen bonds with the three histidine residues in the conserved zinc−binding motif and could chelate the Zn2+ atom of the SVMPs, which could potentially result in inhibition of the venom enzymatic activities and thereby inhibit tissue necrosis.

The ethanolic extract from seed kernels of Thai mango (MSKE) (Mangifera indica L. cv. ‘Fahlun’) (Anacardiaceae) and its major phenolic principle (pentagalloyl glucopyranose) exhibited dose-dependent inhibitory effects on enzymatic activities of phospholipase A2 (PLA2), hyaluronidase and L-amino acid oxidase (LAAO) of Calloselasma rhodostoma (CR) and Naja naja kaouthia (NK)venoms by in vitro tests. The anti-hemorrhagic and anti-dermonecrotic activities of MSKE against both venoms were clearly supported by in vivo tests. Molecular docking studies indicated that the phenolic molecules of the MSKE could selectively bind to the active sites or their proximity, or modify conserved residues that are critical for the catalysis of PLA2, and selectively bind to the LAAO binding pocket of both CR and NK venoms and thereby inhibit their enzymatic activities. The results imply a potential use of MSKE against snake venoms.

The alcoholic extract from seed kernels of Thai mango (Mangifera indica L. cv. ‘Fahlun’) (Anacardiaceae) and its major phenolic principle (pentagalloylglucopyranose) exhibited potent, dose-dependent inhibitory effects on tyrosinase with respect to L-DOPA. Molecular docking studies revealed that the binding orientations of the phenolic principles were in the tyrosinase binding pocket and their orientations were located in the hydrophobic binding pocket surrounding the binuclear copper active site. The results indicated a possible mechanism for their anti-tyrosinase activity which may involve an ability to chelate the copper atoms which are required for the catalytic activity of tyrosinase.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous contaminants of the terrestrial environment that have been designated as Environmental Protection Agency (EPA) Priority Pollutants. In this study, molecular modeling was used to examine the physical and chemical characteristics of soil organic matter (SOM), fulvic acid (FA) and humic acid (HA), as well as their binding interactions with PAHs. The molecular structures of 18 PAHs were built by using the SYBYL 7.0 program and then fully optimized by a semiempirical (AM1) method. A molecular docking program, AutoDock 3.05, was used to calculate the binding interactions between the PAHs, and three molecular structure models including FA (Buffle’s model), HA (Stevenson’s model) and SOM (Schulten and Schnitzer’s model). The π-π interactions and H-bonding interactions were found to play an important role in the intermolecular bonding of the SOM/PAHs complexes. In addition, significant correlations between two chemical properties, boiling point (bp) and octanol/water partition coefficient (Log Kow) and final docking energies were observed. The preliminary docking results provided knowledge of the important binding modes to FA, HA and SOM, and thereby to predict the sorption behavior of PAHs and other pollutants.

The aims of this study were to investigate the potential benefits of antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase activities of a methanolic extract of fresh tea leaves (FTE) (Camellia sinensis L.). The antioxidant capacity was investigated using three different methods at different temperatures. The anti-inflammatory activity was studied in vitro by the inhibition of 5-lipoxygenase assay. The anti-hepatotoxic effect was investigated in CCl4-induced liver injury in rats. The anti-tyrosinase activities of the FTE and its principal phenolic compounds were investigated in l-3,4-dihydroxyphenylalanine (l-DOPA) oxidation by a mushroom tyrosinase. A molecular docking study was conducted to determine how the FTE’s principal catechins interact with the tyrosinase. The FTE exhibited the best shelf life at low temperatures and demonstrated concentration-dependent antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase effects compared to positive references. Treatment of rats with the FTE at 2000 mg/kg/day for 28 consecutive days reversed CCl4-induced oxidative damage in hepatic tissues by lowering the levels of alanine aminotransferase by 69% and malondialdehyde by 90%. Our findings suggest that the FTE has the capacity to scavenge free radicals and can protect against oxidative stress induced by CCl4 intoxication. The docking results were consistent with our in vitro data, indicating the anti-tyrosinase potency of the principal catechins.

Ten dipyridodiazepinone derivatives were synthesized and evaluated for their anti HIV-1 reverse transcriptase activity against wild-type and mutant type enzymes, K103N and Y181C. Two of them were found to be promising inhibitors for HIV-1 RT.