Computational identification of natural product leads that inhibit mast cell chymase: an exclusive plausible treatment for Japanese encephalitis. Issue 4 (4th March 2021)

• Record Type: Journal Article
• Authors: Kant, Kamal; Rawat, Ravi; Bhati, Vipin; Bhosale, Shailesh; Sharma, Dalchand; Banerjee, Subham; Kumar, Anoop
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 39:Issue 4(2021)
• Page Start: 1203
• Page End: 1212
• Publication Date: 2021-03-04
• Subjects: Japanese encephalitis virus -- chymase -- natural chemical entities -- molecular docking -- pharmacokinetic -- toxicity -- molecular dynamics; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2020.1726820
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: A recent research has identified chymase, a mast cell-specific protease as an exclusive novel therapeutic target to prevent Japanese encephalitis virus (JEV) induced encephalitis. Interestingly, JEV activates mast cell specific chymase during its penetration through blood brain barrier (BBB) which eventually guide to viral encephalitis. Hence, in this study, natural chemical entities (NCE) from multiple databases (MPD3, TIPDB and MTDP) were virtually screened for their binding affinity as chymase inhibitors, a promising negotiator for prolong survival against JEV tempted encephalitis. Merged computational programs, Maestro software, QikProp, ProTox and Gromacs were applied to screen the NCEs against target receptor (PDB: 4KP0). Three hits (C00008437, C00014417 and 8141903) were identified after employing a series of sieves such as High Throughput Virtual Screening (HTVS), Standard precision (SP) and Xtra precision (XP) molecular docking simulations followed by desired pharmacokinetic-toxicity profile predictions and molecular dynamics (MD) examinations. Maestro simulations resulted in best three binding energy scores as −11.992 kcal/mol (first ranked; C00008437), −11.673 kcal/mol (second ranked; C00014417) and −11.456 kcal/mol (third ranked; 8141903), respectively. The top three hits revealed an ideal range of pharmacokinetic and toxicity descriptors values. In addition, MD simulations enabled us to confirm top hits higher selectivity toward chymase receptor. In conclusion, this might potentially represent remarkable novel classes with an effective chymase mediated treatment to combat JEV induced encephalitis, which need to justify with further detail studies. Graphical Abstract: Communicated by Ramaswamy H. Sarma