化学
冠状病毒
蛋白酶
效力
严重急性呼吸综合征冠状病毒2型(SARS-CoV-2)
药物发现
2019年冠状病毒病(COVID-19)
结构-活动关系
病毒复制
共晶
化学空间
严重急性呼吸综合征冠状病毒
病毒学
酶
计算生物学
病毒
生物化学
体外
生物
医学
分子
氢键
疾病
病理
传染病(医学专业)
有机化学
作者
Chamandi S. Dampalla,Athri D. Rathnayake,Anushka C. Galasiti Kankanamalage,Yun-Jeong Kim,Krishani Dinali Perera,Harry Nhat Nguyen,Matthew J. Miller,Trent K. Madden,Hunter R. Picard,Hayden A. Thurman,M.M. Kashipathy,Lijun Liu,Kevin P. Battaile,Scott Lovell,Kyeong‐Ok Chang,William C. Groutas
标识
DOI:10.1021/acs.jmedchem.2c00224
摘要
The worldwide impact of the ongoing COVID-19 pandemic on public health has made imperative the discovery and development of direct-acting antivirals aimed at targeting viral and/or host targets. SARS-CoV-2 3C-like protease (3CLpro) has emerged as a validated target for the discovery of SARS-CoV-2 therapeutics because of the pivotal role it plays in viral replication. We describe herein the structure-guided design of highly potent inhibitors of SARS-CoV-2 3CLpro that incorporate in their structure novel spirocyclic design elements aimed at optimizing potency by accessing new chemical space. Inhibitors of both SARS-CoV-2 3CLpro and MERS-CoV 3CLpro that exhibit nM potency and high safety indices have been identified. The mechanism of action of the inhibitors and the structural determinants associated with binding were established using high-resolution cocrystal structures.
科研通智能强力驱动
Strongly Powered by AbleSci AI