Structure based docking and molecular dynamics studies: Peroxisome proliferator-activated receptors –α/γ dual agonists for treatment of metabolic disorders

Abstract

Diabetes is a foremost health problem globally susceptible to increased mortality and morbidity. The present therapies in the antidiabetic class have sound adverse effects and thus, emphasis on the further need to develop effective medication therapy. Peroxisome proliferator-activated receptor alpha-gamma dual approach represents an interesting target for developing novel anti-diabetic drug along with potential anti-hyperlipidimic activity. In the current study, the peroxisome proliferator-activated receptor alpha-gamma agonistic hits were screened by hierarchical virtual screening of drug like compounds followed by molecular dynamics simulation and knowledge-based structure-activity relation analysis. The key amino acid residues of binding pockets of both target proteins were acknowledged as essential and were found to be associated in the key interactions with the most potential dual hit. This dual targeted approach of structure based computational technique was undertaken to identify prevalent promising hits for both targets with binding energy and absorption distribution metabolism excretion prediction supported the analysis of their pharmacokinetic potential. In addition, stability analysis using molecular dynamics simulation of the target protein complexes was performed with the most promising dual targeted hit found in this study. Further, comparative analysis of binding site of both targets was done for the development of knowledge-based structure-activity relationship, which may useful for successful designing of dual agonistic candidates. Abbreviations ADME absorption distribution metabolism excretion

HTVS highthroughput virtual screening

MD molecular dynamics

MMGBSA molecular mechanics generalized bonn solvation accessible

PDB protein data bank

PPAR peroxisome proliferator-activated receptor

RMSD Root mean square deviation

RMSF Root mean square fluctuation

SAR structural activity relationship

SP simple precision

T2DM TypeII diabetes mellitus

XP Extra precision

Communicated by Ramaswamy H. Sarma