化学型
衣壳
效力
计算生物学
立体化学
人类免疫缺陷病毒(HIV)
化学
药物发现
组合化学
对接(动物)
脚手架
生物
生物化学
病毒学
体外
基因
医学
计算机科学
数据库
护理部
色谱法
精油
作者
Thamina Akther,William M. McFadden,Huanchun Zhang,Karen A. Kirby,Stefan G. Sarafianos,Zhengqiang Wang
摘要
HIV-1 capsid protein (CA) is the molecular target of the recently FDA-approved long acting injectable (LAI) drug lenacapavir (GS-6207). The quick emergence of CA mutations resistant to GS-6207 necessitates the design and synthesis of novel sub-chemotypes. We have conducted the structure-based design of two new sub-chemotypes combining the scaffold of GS-6207 and the N-terminal cap of PF74 analogs, the other important CA-targeting chemotype. The design was validated via induced-fit molecular docking. More importantly, we have worked out a general synthetic route to allow the modular synthesis of novel GS-6207 subtypes. Significantly, the desired stereochemistry of the skeleton C2 was confirmed via an X-ray crystal structure of the key synthetic intermediate 22a. Although the newly synthesized analogs did not show significant potency, our efforts herein will facilitate the future design and synthesis of novel subtypes with improved potency.
科研通智能强力驱动
Strongly Powered by AbleSci AI