Computational design of a broad-spectrum multi-epitope vaccine candidate against seven strains of human coronaviruses.

Spike (S) proteins are an attractive target as it mediates the binding of the SARS-CoV-2 to the host through ACE-2 receptors. We hypothesize that the screening of the S protein sequences of all the seven known HCoVs would result in the identification of potential multi-epitope vaccine candidates capable of conferring immunity against various HCoVs. In the present study, several machine learning-based in-silico tools were employed to design a broad-spectrum multi-epitope vaccine candidate targeting the S protein of seven known strains of human coronaviruses. Herein, multiple B-cell epitopes and T-cell epitopes (CTL and HTL) were predicted from the S protein sequences of all seven known HCoVs. Post-prediction they were linked together with an adjuvant to construct a potential broad-spectrum vaccine candidate. Secondary and tertiary structures were predicted and validated, and the refined 3D-model was docked with an immune receptor. The vaccine candidate was evaluated for antigenicity, allergenicity, solubility, and its ability to achieve high-level expression in bacterial hosts. Finally, the immune simulation was carried out to evaluate the immune response after three vaccine doses. The designed vaccine is antigenic (with or without the adjuvant), non-allergenic, binds well with TLR-3 receptor and might elicit a diverse and strong immune response. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03286-0.

Identification of potent HDAC 2 inhibitors using E-pharmacophore modelling, structure-based virtual screening and molecular dynamic simulation.

Histone deacetylase 2 (HDAC 2) of class I HDACs plays a major role in embryonic and neural developments. However, HDAC 2 overexpression triggers cell proliferation by diverse mechanisms in cancer. Over the decades, many pan and class-specific inhibitors of HDAC were discovered. Limitations such as toxicity and differential cell localization of each isoform led researchers to hypothesize that isoform selective inhibitors may be relevant to bring about desired effects. In this study, we have employed the PHASE module to develop an e-pharmacophore model and virtually screened four focused libraries of around 300,000 compounds to identify isoform selective HDAC 2 inhibitors. The compounds with phase fitness score greater than or equal to 2.4 were subjected to structure-based virtual screening with HDAC 2. Ten molecules with docking score greater than -12 kcal/mol were chosen for selectivity study, QikProp module (ADME prediction) and dG/bind energy identification. Compound 1A with the best dock score of -13.3 kcal/mol and compound 1I with highest free binding energy, -70.93 kcal/mol, were selected for molecular dynamic simulation studies (40 ns simulation). The results indicated that compound 1I may be a potent and selective HDAC 2 inhibitor. Further, in vitro and in vivo studies are necessary to validate the potency of selected lead molecule and its derivatives.

Exploration of small-molecule entry disruptors for chikungunya virus by targeting matrix remodelling associated protein.

BACKGROUND AND PURPOSE: A genome-wide clustered regularly interspaced short palindromic repeats- associated protein 9-based screen has revealed that the cell adhesion molecule matrix remodelling associated protein 8 (Mxra8) acts as an entry mediator for many alphaviruses including chikungunya virus. The first X-ray crystal structure reported for Mxra8 a few months ago has a low-resolution of 3.49Å. EXPERIMENTAL APPROACH: Homology modelling of Mxra8 protein was done employing the SWISS-MODEL and PRIME module of Maestro. To design novel Mxra8 inhibitors pharmacophore guided fragment-based drug design and structure-based virtual screening of Food and Drug Administration approved drug libraries were undertaken. Molecular docking and molecular dynamics (MD) simulations study were carried out to validate the findings. FINDINGS / RESULTS: The molecule H1a (dock score: -6.137, binding energy: -48.95 kcal/mol, and PHASE screen score: 1.528816) was identified as the best hit among the fragment-based designed ligands. Structure- based virtual screening suggested histamine, epinephrine, and capreomycin as potential hits which could be repurposed as Mxra8 inhibitor. MD simulations study suggested that only small molecules like histamine could be a potential inhibitor of Mxra8. H-bond interaction with Arg58 and Glu200 amino acid residues seems to be crucial for effective binding. CONCLUSION AND IMPLICATIONS: To the best of our knowledge, this is the first report on the design of novel inhibitors against Mxra8 protein to tackle the menace of alphaviruses infections. This design strategy could be used for structure-based drug design against other apo-proteins. This study also advances the application of in silico tools in the field of drug repurposing.

Design, development, drug-likeness, and molecular docking studies of novel piperidin-4-imine derivatives as antitubercular agents.

Tuberculosis remains one of the major grievous diseases worldwide. The emergence of resistance to antituberculosis drugs emphasize the necessity to discover new therapeutic agents for preferential tuberculosis therapy. In this study, various novel 1-(1H-benzimidazol-2-ylmethyl) piperidin-4-imine derivatives were developed and checked for favorable pharmacokinetic parameters based on drug-likeness explained by Lipinski's rule of five. All 20 of the novel chemical entities were found to possess a favorable pharmacokinetic profile since they were not violating Lipinski's rule of five. The title compounds were also synthesized, characterized, and tested for ex vivo antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The results revealed that four compounds (2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene] hydrazinecarbothioamide, 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]-N-hydroxy-hydrazinecarbo-thioamide, 1-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]guanidine, and 2-[1-(1H-benzimidazol-2-ylmethyl)piperidin-4-ylidene]hydrazinecarboxamide) were the most potent (minimum inhibitory concentration 6.25 µg/mL) antitubercular agents, with less toxicity (selectivity index more than 10). The molecules were also subjected to three-dimensional molecular docking on the crystal structure of enoyl-acyl carrier protein (EACP) reductase enzyme (code 1ZID, Protein Data Bank), which represents a good prediction of the interactions between the molecules and EACP reductase with minimum binding energy.

Synthesis and evaluation of urea and thiourea derivatives of oxazolidinones as antibacterial agents.

Urea and thiourea derivatives of oxazolidinones were synthesized and their inhibitory activity (MIC) was determined on the bacterial strains which includes clinical isolates and quality control organisms. The structure activity relationships were studied and a 3D-QSAR model was built using Genetic Function Approximation. Interestingly found that electron withdrawing groups at the ortho position of the phenyl ring enhances the activity.