Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors
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DOI：
10.1126/science.abo7201
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发表时间：
2023-11-10
期刊：
影响因子：
56.9
通讯作者：
von Delft, Frank
中科院分区：
文献类型：
--
作者：
Boby, Melissa L.;Fearon, Daren;von Delft, Frank
我们报告了COVID Moonshot的结果，这是一项完全开放科学，众包和结构启用的药物发现活动，针对严重急性呼吸道综合征冠状病毒2（SARS-CoV-2）主要蛋白酶。我们发现了一种非共价，非肽类抑制剂支架与铅样的性能，是从目前的主要蛋白酶抑制剂的区别。我们的方法利用了众包、机器学习、亿级分子模拟以及高通量结构生物学和化学。我们生成了SARS-CoV-2主要蛋白酶的结构可塑性的详细地图，多种化学型的广泛结构-活性关系，以及丰富的生化活性数据。该活动的所有化合物设计（> 18，000个设计），晶体学数据（>490个配体结合的X射线结构），测定数据（> 10，000个测量）和合成分子（>2400个化合物）都被快速公开地共享，为未来的新冠病毒药物发现创造了丰富，开放和无知识产权的知识库。
We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.