Investigations of retinoic acid receptor-related orphan receptor-gamma t (RORγt) agonists: a combination of 3D-QSAR, molecular docking and molecular dynamics

Abstract

Retinoic acid receptor-related orphan receptor-gamma t (RORγt) is an attractive target for Th17-driven autoimmune diseases. In the present work, a series of RORγt agonists were investigated by a molecular modeling study combining three-dimensional quantitative structure activity relationship (3D-QSAR), molecular docking, molecular dynamics (MD) simulations and binding free energies to get insight into the molecular features that would promote binding activity. The optimum comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models for 3D-QSAR studies possess satisfactory predictive ability, with R2 cv=0.615, R2 pred=0.8702 for CoMFA, and R2 cv=0.670, R2 pred=0.7683 for CoMSIA model, respectively. In addition, molecular docking studies, molecular dynamics simulations and binding free energies were used to find the actual conformations of compounds in the active site of RORγt, and key residues GLN-286, LEU-287, HIS-323 and ARG-367 for higher binding activity were pointed out. The predicted models will help us to understand the structural requirements of RORγt agonists for the designing of better active compounds. Communicated by Ramaswamy H. Sarma