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

Retinoic acid receptor-related orphan receptor-gamma t (ROR gamma t) is an attractive target for Th17-driven autoimmune diseases. In the present work, a series of ROR gamma t 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 R-cv(2)=0.615, R-pred(2)=0.8702 for CoMFA, and R-cv(2)=0.670, R-pred(2)=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 ROR gamma t, 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 ROR gamma t agonists for the designing of better active compounds.

Automated summary

In this study, various ROR gamma t agonists were investigated using multiple molecular modeling techniques to understand the structural requirements for designing better active compounds. The CoMFA and CoMSIA models showed satisfactory predictive ability, while molecular docking and dynamics simulations identified key residues for higher binding activity in the active site of ROR gamma t.