Mining of potential dipeptidyl peptidase-IV inhibitors as anti-diabetic agents using integrated in silico approaches. Issue 18 (11th December 2020)

• Record Type: Journal Article
• Authors: Sharma, Shweta; Srivastava, Shubham; Shrivastava, Apeksha; Malik, Ruchi; Almalki, Faisal; Saifullah, Khalid; Alam, Mohammad Mumtaz; Shaqiquzzaman, Mohammad; Ali, Shakir; Akhter, Mymoona
• Is Part Of: Journal of biomolecular structure & dynamics. Volume 38:Issue 18(2020)
• Page Start: 5349
• Page End: 5361
• Publication Date: 2020-12-11
• Subjects: Dipeptidyl peptidase-IV -- virtual screening -- ADME -- molecular dynamics -- pharmacophore mapping -- PBVS; Biomolecules -- Periodicals; Molecular structure -- Periodicals; Molecular Biology -- Periodicals; Biomechanics -- Periodicals; 572
• DOI: 10.1080/07391102.2019.1701553
• Languages: English
• ISSNs: 0739-1102

Abstract

Abstract: The dipeptidyl peptidase-IV (DPP-IV) family of receptors possesses a large binding cavity that imparts promiscuity for number of ligand binding which is not common to other receptors. This feature increases the challenge of using computational methods to identify DPP-IV inhibitors, therefore using both pharmacophore and structure-based screening seems to be a reliable approach. Mining of novel DPP-IV inhibitors by integrating both of these in silico techniques was reported. Pharmacophore model (Model_008) obtained from structurally diverse reported compounds was used as a template for screening of MolMall database followed by structure-based screening against PDB ID: 5T4E. After absorption, distribution, metabolism and excretion (ADME) analysis of shortlisted compounds, consensus docking and molecular mechanics/generalized born surface area studies were carried out. The results of the docking studies obtained were comparable to that of the reference ligand. Out of nine hits identified, only one hit (ID MolMall-20062 ) was available which was procured through exchange program. Molecular dynamic simulation studies of the procured hit revealed its good selectivity and stability in DPP-IV binding pocket and interactions observed with important amino acids viz., Trp629, Lys544 and Arg125. Biological testing of the compound MolMall-20062 showed promising DPP-IV inhibition activity with IC50 : 6.2 µM. Compound MolMall-20062 could be taken as a good lead for the development of DPP-IV inhibitors. Abbreviations: ADME absorption, distribution, metabolism and excretion ChEBI chemical entities of biological interest DPP-IV dipeptidyl peptidase IV DISCOtech distance comparisons HTVS high throughput virtual screening MD molecular dynamics MM-GBSA molecular mechanics‐generalized born surface area OGTT oral glucose tolerance test PBVS pharmacophore-based virtual screening PDB protein data bank RMSD root mean square deviation ROC receiver operating characteristics SP standard precision SBVS structure-based virtual screening VS virtual screening XP extra precision Communicated by Ramaswamy H. Sarma