A high-throughput screen of the NIH molecular libraries sample collection and subsequent optimization of a lead dipeptide-like series of severe acute respiratory syndrome (SARS) main protease (3CLpro) inhibitors led to the identification of probe compound ML188 (16-(R), (R)-N-(4-(tert-butyl)phenyl)-N-(2-(tert-butylamino)-2-oxo-1-(pyridin-3-yl)ethyl)furan-2-carboxamide, Pubchem CID: 46897844). Unlike the majority of reported coronavirus 3CLpro inhibitors that act via covalent modification of the enzyme, 16-(R) is a noncovalent SARS-CoV 3CLpro inhibitor with moderate MW and good enzyme and antiviral inhibitory activity. A multicomponent Ugi reaction was utilized to rapidly explore structure–activity relationships within S_1′, S₁, and S₂ enzyme binding pockets. The X-ray structure of SARS-CoV 3CLpro bound with 16-(R) was instrumental in guiding subsequent rounds of chemistry optimization. 16-(R) provides an excellent starting point for the further design and refinement of 3CLpro inhibitors that act by a noncovalent mechanism of action.

中文翻译：

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一系列 N-(叔丁基)-2-(N-芳基氨基)-2-(吡啶-3-基)乙酰胺 (ML188) 作为有效非共价小分子抑制剂的发现、合成和基于结构的优化严重急性呼吸系统综合症冠状病毒 (SARS-CoV) 3CL 蛋白酶

NIH 分子文库样品收集的高通量筛选和严重急性呼吸系统综合症 (SARS) 主要蛋白酶 (3CLpro) 抑制剂类先导二肽系列的后续优化导致探针化合物 ML188 ( 16-( R )的鉴定，( R ) -N- (4-(叔丁基)苯基) -N- (2-(叔丁基氨基)-2-氧代-1-(吡啶-3-基)乙基)呋喃-2-甲酰胺， Pubchem CID：46897844）。与大多数报道的冠状病毒 3CLpro 抑制剂不同，它们通过酶的共价修饰起作用，16-( R )是一种非共价 SARS-CoV 3CLpro 抑制剂，具有中等分子量和良好的酶和抗病毒抑制活性。利用多组分 Ugi 反应快速探索 S _1'、S ₁和 S ₂酶结合口袋内的结构-活性关系。与16-( R )结合的 SARS-CoV 3CLpro 的 X 射线结构有助于指导后续几轮化学优化。16-( R )为进一步设计和改进通过非共价作用机制发挥作用的 3CLpro 抑制剂提供了极好的起点。