In Silico Molecular Dynamics and 3D-QSAR Study on Thiazolidinedione Derivatives as Dual Inhibitors of DPP IV and PTP1B (DDPI's) for the Management of T2DM

Abstract

Simultaneous inhibition of dipeptidyl peptidase IV and protein tyrosine phosphatase 1B as DDPI's emerged as a therapeutic intervention for the management of T2DM. In the present study, we have employed molecular dynamics simulation in conjugation with the field-based 3D QSAR studies on a dataset having DDPI activities to identify the spatial fingerprints of target-specific thiazolidinedione analogs. Separate contours were generated for both DPP IV and PTP1B showing respective pharmacophoric structural requirements for optimal inhibitory activity. These developed 3D QSAR models also showed good statistical measures (DPP IV: r² = 0.9468; q² = 0.7173, and PTP1B: r² = 0.9718; q² = 0.819) with the excellent predictive ability with PLS-generated validation constraints. Comparative steric and electrostatic features were elucidated using respective contour maps for selective target-specific favorable activity. Furthermore, molecular docking was used for elucidating the mode of binding as DDPI's to DPP IV and PTP1B, along with MD simulation (200 ns) analysis such as RMSD, RMSF, R_g, SASA, PCA, and FEL. These studies revealed that all the protein-ligand docked complexes elicited an overall better stability as compared to reference ligand (vildagliptin or ertiprotafib) complexes. Molecular docking studies revealed that compound 24 (DPP IV: −150.667 kcal/mol; PTP1B: −142.792 kcal/mol) showed maximum affinity toward both the proteins DPP IV and PTP1B, as compared to their respective standard inhibitor, i.e., vildagliptin −99.9843 kcal/mol and ertiprotafib −125.399 kcal/mol, respectively. A comparative study of these developed multitargeted QSAR models along with molecular docking and dynamics study were employed for the optimization of drug candidates as DDPI's. Compound 24 showed most stable behavior in the binding pockets of both the enzymes, as compared to their respective standard inhibitors. This study will be helpful in designing novel DDPIs with appropriately substitute thiazolidinedione for the management of T2DM. The designed compound YSR-14 exhibited the predicted IC₅₀ values of 0.143 µM in DPP IV and 0.158 µM in PTP1B along with their excellent binding affinity against both targets.