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首页> 外文期刊>Journal of Computer-Aided Molecular Design >Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking
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Target identification for repurposed drugs active against SARS-CoV-2 via high-throughput inverse docking

机译：通过高通量反向对接对 SARS-CoV-2 活性的再利用药物进行靶标鉴定

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摘要

Screening already approved drugs for activity against a novel pathogen can be an important part of global rapid-response strategies in pandemics. Such high-throughput repurposing screens have already identified several existing drugs with potential to combat SARS-CoV-2. However, moving these hits forward for possible development into drugs specifically against this pathogen requires unambiguous identification of their corresponding targets, something the high-throughput screens are not typically designed to reveal. We present here a new computational inverse-docking protocol that uses all-atom protein structures and a combination of docking methods to rank-order targets for each of several existing drugs for which a plurality of recent high-throughput screens detected anti-SARS-CoV-2 activity. We demonstrate validation of this method with known drug-target pairs, including both non-antiviral and antiviral compounds. We subjected 152 distinct drugs potentially suitable for repurposing to the inverse docking procedure. The most common preferential targets were the human enzymes TMPRSS2 and PIKfyve, followed by the viral enzymes Helicase and PLpro. All compounds that selected TMPRSS2 are known serine protease inhibitors, and those that selected PIKfyve are known tyrosine kinase inhibitors. Detailed structural analysis of the docking poses revealed important insights into why these selections arose, and could potentially lead to more rational design of new drugs against these targets.
机译：筛选已获批准的药物对新型病原体的活性可能是全球大流行快速反应战略的重要组成部分。这种高通量再利用筛选已经确定了几种具有对抗SARS-CoV-2潜力的现有药物。然而，将这些命中物向前推进，以便可能开发成专门针对这种病原体的药物，需要明确识别其相应的靶标，而高通量筛选通常不会设计用于揭示这一点。我们在这里提出了一种新的计算反向对接协议，该协议使用全原子蛋白质结构和对接方法的组合，对几种现有药物中的每种靶标进行排序，其中多个最近的高通量筛选检测到抗 SARS-CoV-2 活性。我们证明了该方法使用已知的药物-靶标对（包括非抗病毒和抗病毒化合物）进行验证。我们对 152 种可能适合重新利用的不同药物进行了反向对接程序。最常见的优先靶标是人类酶TMPRSS2和PIKfyve，其次是病毒酶解旋酶和PLpro。选择TMPRSS2的所有化合物都是已知的丝氨酸蛋白酶抑制剂，选择PIKfyve的化合物是已知的酪氨酸激酶抑制剂。对对接姿势的详细结构分析揭示了为什么会出现这些选择的重要见解，并可能导致针对这些靶点的新药的更合理设计。

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