title: 3D-QSAR, molecular docking and molecular dynamics studies of a series of RORγt inhibitors.
abstract: The discovery of clinically relevant inhibitors of retinoic acid receptor-related orphan receptor-gamma-t (RORγt) for autoimmune diseases therapy has proven to be a challenging task. In the present work, to find out the structural features required for the inhibitory activity, we show for the first time a three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations for a series of novel thiazole/thiophene ketone amides with inhibitory activity at the RORγt receptor. The optimum CoMFA and CoMSIA models, derived from ligand-based superimposition I, exhibit leave-one-out cross-validated correlation coefficient (R(2)cv) of .859 and .805, respectively. Furthermore, the external predictive abilities of the models were evaluated by a test set, producing the predicted correlation coefficient (R(2)pred) of .7317 and .7097, respectively. In addition, molecular docking analysis was applied to explore the binding modes between the inhibitors and the receptor. MD simulation and MM/PBSA method were also employed to study the stability and rationality of the derived conformations, and the binding free energies in detail. The QSAR models and the results of molecular docking, MD simulation, binding free energies corroborate well with each other and further provide insights regarding the development of novel RORγt inhibitors with better activity.
authors.affiliation: a The State Key Laboratory of Food Science and Technology , Jiangnan University , Wuxi 214000 , China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Shi
authors.forename: Guowei
authors.initials: G
authors.lastname: Le
mesh_terms: D001665:Binding Sites; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry; D013876:Thiophenes / Q000737:chemistry
chemical_list: D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D013844:Thiazoles; D013876:Thiophenes
keywords: CoMFA; CoMSIA; MM/PBSA; RORγt; molecular docking; molecular dynamics