分析 SARS-CoV-2 主要蛋白酶的 3D 结构揭示了 COVID-19 药物发现中配体结合的结构特征。

Analyzing 3D structures of the SARS-CoV-2 main protease reveals structural features of ligand binding for COVID-19 drug discovery.

机构信息

National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR 72079, USA.

Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.

出版信息

Drug Discov Today. 2023 Oct;28(10):103727. doi: 10.1016/j.drudis.2023.103727. Epub 2023 Jul 27.

DOI:10.1016/j.drudis.2023.103727

PMID:37516343

Abstract

The severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) main protease has an essential role in viral replication and has become a major target for coronavirus 2019 (COVID-19) drug development. Various inhibitors have been discovered or designed to bind to the main protease. The availability of more than 550 3D structures of the main protease provides a wealth of structural details on the main protease in both ligand-free and ligand-bound states. Therefore, we examined these structures to ascertain the structural features for the role of the main protease in the cleavage of polyproteins, the alternative conformations during main protease maturation, and ligand interactions in the main protease. The structural features unearthed could promote the development of COVID-19 drugs targeting the SARS-CoV-2 main protease.

摘要

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 主要蛋白酶在病毒复制中起着至关重要的作用，已成为针对 2019 年冠状病毒病 (COVID-19) 的药物开发的主要靶点。已经发现或设计了各种抑制剂来与主要蛋白酶结合。超过 550 个主要蛋白酶的三维结构的可用性提供了大量配体结合和非配体结合状态下主要蛋白酶的结构细节。因此，我们检查了这些结构，以确定主要蛋白酶在多蛋白切割、主要蛋白酶成熟过程中的替代构象以及主要蛋白酶中配体相互作用中的结构特征。挖掘出的结构特征可以促进针对 SARS-CoV-2 主要蛋白酶的 COVID-19 药物的开发。