学术报告题目：Structure-Based Discovery of Potent RORgt Modulators
- From Drug Concept to Clinic Candidate
VP, Head of Integrated Biology
BioDuro, LLC. (润诺生物科技(上海)有限公司，保诺科技(北京)有限公司)
报告摘要：The nuclear receptor retinoid acid receptor-related orphan receptor γt (RORγt) is a master regulator of the Th17/IL-17 pathway that plays crucial roles in the pathogenesis of autoimmunity. RORγt has recently emerged as a highly promising target for treatment of a number of autoimmune diseases. Through high-throughput screening, we had identified several classes of inverse agonists for RORγt. In this seminar I will discuss the molecular level mechanism of action for these inverse agonists as revealed by X-ray crystallography, NMR and ab initio computational studies. I will show that nuclear receptor structure and function are dictated by a dynamic conformational equilibrium and that subtle changes in ligand structures can shift this equilibrium in opposite directions, leading to a functional switch from inverse agonists to agonists. I will also show the challenges and ultimate success to optimize RORγt drug leads to a clinical candidate, highlighting the roles of structure-based design and fragment-based screening in overcoming the challenges during the process.