片段(逻辑)
药物发现
精化
计算生物学
铅化合物
计算机科学
化学
立体化学
组合化学
生物
算法
生物化学
体外
艺术
人文学科
作者
Chris Smith,Svitlana Kulyk,Misbha Ud Din Ahmad,Valentina Arkhipova,James G. Christensen,Robin J. Gunn,Anthony Ivetac,John M. Ketcham,Jon Kuehler,J. David Lawson,Nicole C. Thomas,Xiaolun Wang,Matthew A. Marx
出处
期刊:RSC medicinal chemistry
[The Royal Society of Chemistry]
日期:2022-01-01
卷期号:13 (12): 1549-1564
被引量:3
摘要
Here we describe the early stages of a fragment-based lead discovery (FBLD) project for a recently elucidated synthetic lethal target, the PRMT5/MTA complex, for the treatment of MTAP-deleted cancers. Starting with five fragment/PRMT5/MTA X-ray co-crystal structures, we employed a two-phase fragment elaboration process encompassing optimization of fragment hits and subsequent fragment growth to increase potency, assess synthetic tractability, and enable structure-based drug design. Two lead series were identified, one of which led to the discovery of the clinical candidate MRTX1719.
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