Theoretical study of the adiponectin receptors: binding site characterization and molecular dynamics of possible ligands for drug design

Abstract

The two adiponectin receptors (AdipoR1 and AdipoR2) have been implicated in glucose and lipid regulation involved in several metabolic pathologies including type II diabetes. Their exact biochemical functions and mechanisms remain poorly understood. Moreover, these receptors do not yet have data on possible co-crystallized active ligands. In this study, we applied different computational methodologies to address three main unanswered questions: first, the localization and validation of possible binding sites; second, the generation of novel ligands with amenable characteristics to target the receptors; and third, the determination of important chemical interactions between the ligands and the receptors. Computational analysis of the binding site reveals that the residues triad R267, F271, and Y310 could be responsible for changes in the spatial arrangement and geometry of the binding pocket in AdipoR1. Molecular docking results in high docking scores of − 13.6 and − 16.5 kcal/mol for the top best ligands in AdipoR1 and AdipoR2 respectively. Finally, molecular dynamics suggests that hydrolytic activity may be possible with these compounds and that this reaction could be mediated by aspartic acid residues. The two adiponectin receptors have an endogenous protein ligand, adiponectin. However the synthesis is expensive and technically challenging. Although some debatable agonists have been proposed investigations of suitable synthetic ligands are indeed, very much needed for targeting these receptors and their associate pathologies and metabolic pathways. Furthermore, these findings provide a framework for further biochemical investigations of amenable compounds for drug discovery in order to target these receptors and their associated pathologies.