In silico strategies for probing novel DPP-IV inhibitors as anti-diabetic agents. Issue 6 (31st March 2021)

• Record Type: Journal Article
• Authors: Sharma, Shweta; Srivastav, Shubham; Singh, Garima; Singh, Smrita; Malik, Ruchi; Alam, Mohammad Mumtaz; Shaqiquzamman, Mohammad; Ali, Shakir; Akhter, Mymoona
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 39:Issue 6(2021)
• Page Start: 2118
• Page End: 2132
• Publication Date: 2021-03-31
• Subjects: Dipeptidyl peptidase-IV -- Virtual screening -- ADME -- Molecular dynamic -- Pharmacophore mapping -- synthetic accessibility; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2020.1751714
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: Identification of new DPP-IV inhibitors by integrating validated in silico approach is being presented herein. Novel hits were identified by combining pharmacophore and structure based virtual screening of ZINC and Knowledge Base in house database followed by ADME profiling, consensus docking studies. Six potential hits were identified and analysed for their synthetic accessibility score, novelty analysis and pan assay interference compounds filtration. Out of six, three hits viz., ZINC25060187, ZINC53746227 and KB-10 were analysed for stability studies using Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and Molecular Dynamics (MD) simulation. The simulation studies of the identified hits revealed that these hits have good selectivity and stability in DPP-IV binding pocket. Important interactions with amino acids viz., Tyr547, Glu205 and Glu206 similar to co-crystallized ligand were also observed. One of the hits viz., KB-10 was synthesized and evaluated for its biological potential. The compound KB-10 showed good DPP-IV inhibition in both in vitro and in vivo studies with IC50 : 22.69 µM. This study supports the fact that these techniques hold potential for efficient screening of compounds with unknown affinity for DPP-IV that could serve as candidates for therapeutic development. Communicated by Ramaswamy H. Sarma