小柯机器人

中国科学院分子细胞科学卓越创新中心汪胜等研究人员合作发现，基于灵活支架的化学信息学方法可用于多药理药物设计。2024年3月28日，国际知名学术期刊《细胞》在线发表了这一成果。

研究人员提出了一种基于柔性支架的化学信息学方法（FSCA），用于合理设计多药理药物。FSCA包括使用不同的结合姿态将柔性支架与不同的受体相匹配，以IHCH-7179为例，它在5-HT_2AR上采用了“向下弯曲”的结合姿态来作为拮抗剂，而在5-HT_1AR上采用了“向上伸展”的结合姿态来作为激动剂。IHCH-7179通过阻断5-HT_2AR以缓解精神活性症状，激活5-HT_1AR以缓解认知障碍，在缓解小鼠认知障碍和精神活性症状方面取得了良好的效果。

通过分析胺能受体结构，研究人员确定了两个特征基团，即“激动剂过滤器”和“构象塑造器”，它们决定配体的结合姿势并预测胺能受体的活性。有了这些基团，FSCA可用于设计其他受体的多药理配体。

据悉，有效治疗复杂的中枢神经系统（CNS）疾病需要具有多药理学和多功能性的药物，然而设计此类药物仍然是一项挑战。

附：英文原文

Title: Flexible scaffold-based cheminformatics approach for polypharmacological drug design

Author: Zhangcheng Chen, Jing Yu, Huan Wang, Peiyu Xu, Luyu Fan, Fengxiu Sun, Sijie Huang, Pei Zhang, He Huang, Shuo Gu, Bowen Zhang, Yue Zhou, Xiaobo Wan, Gang Pei, H. Eric Xu, Jianjun Cheng, Sheng Wang

Issue&Volume: 2024-03-28

Abstract: Effective treatments for complex central nervous system (CNS) disorders require drugswith polypharmacology and multifunctionality, yet designing such drugs remains a challenge.Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for therational design of polypharmacological drugs. FSCA involves fitting a flexible scaffoldto different receptors using different binding poses, as exemplified by IHCH-7179,which adopted a “bending-down” binding pose at 5-HT2AR to act as an antagonist and a “stretching-up” binding pose at 5-HT1AR to function as an agonist. IHCH-7179 demonstrated promising results in alleviatingcognitive deficits and psychoactive symptoms in mice by blocking 5-HT2AR for psychoactive symptoms and activating 5-HT1AR to alleviate cognitive deficits. By analyzing aminergic receptor structures, weidentified two featured motifs, the “agonist filter” and “conformation shaper,” whichdetermine ligand binding pose and predict activity at aminergic receptors. With thesemotifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.

DOI: 10.1016/j.cell.2024.02.034

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00237-X