Exploring the potent inhibitors and binding modes of phospholipase A2 through in silico investigation.

Snake venom of Naja naja comprises of several types of enzymes, and among them, water-soluble proteolytic enzyme, phospholipase A2 (PLA2), is noteworthy for its numerous adverse effects, such as cytotoxicity, cardiotoxicity, hemolytic, anti-coagulant, and hypotensive effects, including being highly potent as a neurotoxin. Limited anti-venom therapy (with their lower efficacy) has attracted considerable pharmacological interest to develop potent inhibitors of PLA2. Thus, 34 experimentally proven and diverse synthetic inhibitors of PLA2 were screened primarily on the basis of Glide extra precision docking and MM-GBSA rescoring function. Then, ten potential hits were subjected to induced fit docking, in which top three potential inhibitors were considered, and those were found to interact with Ca2+, disulfide binding site, and phosphatidylcholine activation sites, thereby, possibly disrupting the catalytic activity of Ca2+ as well as the inflammatory functions of PLA2. These compounds showed positive remarks on various physiochemical properties and pharmacologically relevant descriptors. Gap energy and thermodynamic properties were investigated by employing density functional theory for all compounds to understand their chemical reactivity and thermodynamic stability. Molecular dynamics simulation was performed for 100 ns in order to evaluate the stability and binding modes of docked complexes, and the energy of binding was calculated through MM-PBSA analysis. On the whole, the proposed compounds could be used for targeted inhibition. Communicated by Ramaswamy H. Sarma.

Quantum chemical calculation and binding modes of H1R; a combined study of molecular docking and DFT for suggesting therapeutically potent H1R antagonist.

Histamine-1 receptor (H1R) belongs to the family of rhodopsin-like G-protein-coupled receptors expressed in cells that mediates allergies and other pathophysiological diseases. For alleviation of allergic symptoms, H1R antagonists are therapeutic drugs; of which the most frequently prescribed are second generation drugs, such as; Cetirizine, Loratadine, Hydroxyzine, Desloratadine, Bepotastine, Acrivastine and Rupatadine. To understand their potency, binding affinity and interaction; we have employed molecular docking and quantum chemical study such as; Induced-fit docking and calculation of quantum chemical descriptors. This study also introduces the binding site characterization of H1R, with its known antagonists and Curcumin (our proposed alternative H1R antagonist); useful for future drug target site. The interactive binding site residues of H1R are found to be; Lys-191, Tyr-108, Asp-107, Tyr-100, Lys-179, Lys-191, Thr-194, Trp-428, Phe-432, Tyr-458, Hie-450, with most of these shown to be inhibited by naturally-occurring compound curcumin. Amongst the FDA approved drugs, Hydroxyzine showed best ligand binding affinity, calculated as - 141.491 kcal/mol and naturally occurring compound, Curcumin showed binding affinity of - 87.046 kcal/mol. The known antagonists of H1R has been used for hypothesizing curcumin as naturally occurring lead compound for the target using accurate molecular docking simulation study. Though the pharmacological action of known inhibitor is already established, they could differ from their reactivity, which we have also focused in our study for predicting drug reactivity.

Assessment of structurally and functionally high-risk nsSNPs impacts on human bone morphogenetic protein receptor type IA (BMPR1A) by computational approach.

BMPR1A (BMP type 1 receptor) is a transmembrane cell-surface receptor also known as ALK3 (activin-like kinases-3) encodes for a type I serine/threonine kinase receptor and a member of the transforming growth-factor ß-receptor (TGF-ß) super family. The BMPR1A has a significant interaction with BMP-2 for protein activity and also has a low affinity with growth and differentiation factor 5 (GDF5); positively regulates chondrocyte differentiation. The genetic variations can alter the structure and function of the BMPR1A gene that causes several diseases such as juvenile polyposis syndrome or hereditary cancer-predisposing syndrome. The current study was carried out to identify potential deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) in BMPR1A by implementing different computational algorithms such as SIFT, PolyPhen2, SNAP2, PROVEAN, PhD-SNP, SNPs&GO, nsSNPAnalyzer, and P-Mut. From 205 nsSNPs in BMPR1A, 7 nsSNPs (C76Y, C124R, C124Y, C376Y, R443C, R480W, and W487R) were predicted as deleterious in 8 prediction algorithms. The Consurf analysis showed that selected 7 nsSNPs were present in the highly conserved regions. Molecular dynamics simulation analysis also performed to explore conformational changes in the variant structure with respect to its native structure. According to the MDS result, all variants flexibility and rigidity were unbalanced, which may alter the structural and functional behavior of the native protein. Although, three nsSNPs i.e., C124R, C376Y, and R443C have already been reported in patients associated with JPS, but their structural and functional molecular studies remain uncharacterized. Therefore, the findings of this study can provide a better understanding of uncharacterized nsSNPS and to find their association with disease susceptibility and also facilitate to the researchers for designing or developing the target dependent drugs.