Fragment-based design of selective GPCR ligands guided by free energy simulations
作者:Pierre Matricon、Duc Duy Vo、Zhan-Guo Gao、Jan Kihlberg、Kenneth A. Jacobson、Jens Carlsson
DOI:10.1039/d1cc03202j
日期:——
Fragment-based drug discovery relies on successful optimization of weakly binding ligands for affinity and selectivity. Herein, we explored strategies for structure-based evolution of fragments binding to a G protein-coupled receptor. Molecular dynamics simulations combined with rigorous free energy calculations guided synthesis of nanomolar ligands with up to >1000-fold improvements of binding affinity
基于片段的药物发现依赖于弱结合配体的亲和力和选择性的成功优化。在此,我们探索了与 G 蛋白偶联受体结合的片段的基于结构的进化策略。分子动力学模拟结合严格的自由能计算指导纳米摩尔配体的合成,结合亲和力提高了 1000 倍以上,亚型选择性接近 40 倍。