Insights of ligand binding in modeled h5-HT1A receptor: homology modeling, docking, MM-GBSA, screening and molecular dynamics. Issue 22 (12th December 2022)

• Record Type: Journal Article
• Authors: Jha, Preeti; Chaturvedi, Shubhra; Bhat, Ruchika; Jain, Nidhi; Mishra, Anil K.
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 40:Issue 22(2022)
• Page Start: 11625
• Page End: 11637
• Publication Date: 2022-12-12
• Subjects: h5-HT1A receptor -- homology modeling -- docking -- ligand binding -- molecular dynamics; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2021.1961865
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: The pharmacologically characterized receptor subtype of the serotonin family, the 5HT1A receptor is implicated in the pathophysiology and treatment of depression and anxiety-related disorders. Being the most extensively targeted receptor for developing novel antidepressants and anxiolytics, a near-ideal theoretical model can aid in high-throughput screening of promising drug candidates. However, the design of potential drug candidates suffers owing to a lack of complete structural information. In this work, homology models of 5-HT1A receptor are generated using two distinct alignments (CW and PSTA) and model building methods (KB and EB). The developed models are validated for virtual screening using a ligand dataset of agonists and antagonists. The best-suited model was efficient in discriminating agonist/antagonist binding. Correlation plots between pKi and docking (R 2 agonist ≥ 0.6, R 2 antagonist ≥ 0.7) and MM-GBSA dG bind values (R 2 agonist ≥ 0.5, R 2 antagonist ≥ 0.7) revealed optimum corroboration between in vitro and in silico outcomes, which further suggested the usefulness of the developed model for the design of high-affinity probes for the neurological disorders. Communicated by Ramaswamy H. Sarma