Hybrid In Silico Approach Reveals Novel Inhibitors of Multiple SARS-CoV-2 Variants,ACS Pharmacology & Translational Science

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Hybrid In Silico Approach Reveals Novel Inhibitors of Multiple SARS-CoV-2 Variants
ACS Pharmacology & Translational Science ( IF 4.9 ) Pub Date : 2021-09-17 , DOI: 10.1021/acsptsci.1c00176
Sankalp Jain ₁ , Daniel C Talley ₁ , Bolormaa Baljinnyam ₁ , Jun Choe ₁ , Quinlin Hanson ₁ , Wei Zhu ₁ , Miao Xu ₁ , Catherine Z Chen ₁ , Wei Zheng ₁ , Xin Hu ₁ , Min Shen ₁ , Ganesha Rai ₁ , Matthew D Hall ₁ , Anton Simeonov ₁ , Alexey V Zakharov ₁

Affiliation

The National Center for Advancing Translational Sciences (NCATS) has been actively generating SARS-CoV-2 high-throughput screening data and disseminates it through the OpenData Portal (https://opendata.ncats.nih.gov/covid19/). Here, we provide a hybrid approach that utilizes NCATS screening data from the SARS-CoV-2 cytopathic effect reduction assay to build predictive models, using both machine learning and pharmacophore-based modeling. Optimized models were used to perform two iterative rounds of virtual screening to predict small molecules active against SARS-CoV-2. Experimental testing with live virus provided 100 (∼16% of predicted hits) active compounds (efficacy > 30%, IC₅₀ ≤ 15 μM). Systematic clustering analysis of active compounds revealed three promising chemotypes which have not been previously identified as inhibitors of SARS-CoV-2 infection. Further investigation resulted in the identification of allosteric binders to host receptor angiotensin-converting enzyme 2; these compounds were then shown to inhibit the entry of pseudoparticles bearing spike protein of wild-type SARS-CoV-2, as well as South African B.1.351 and UK B.1.1.7 variants.

中文翻译：

混合计算机方法揭示了多种 SARS-CoV-2 变体的新型抑制剂

国家转化科学促进中心 (NCATS) 一直在积极生成 SARS-CoV-2 高通量筛查数据，并通过 OpenData 门户 (https://opendata.ncats.nih.gov/covid19/) 进行传播。在这里，我们提供了一种混合方法，利用机器学习和基于药效团的建模，利用来自 SARS-CoV-2 细胞病变效应降低测定的 NCATS 筛选数据来构建预测模型。使用优化模型进行两轮迭代虚拟筛选，以预测对 SARS-CoV-2 具有活性的小分子。使用活病毒进行的实验测试提供了 100 种（~预测命中的 16%）活性化合物（功效 > 30%，IC ₅₀ ≤ 15 μM）。对活性化合物的系统聚类分析揭示了三种有前途的化学型，这些化学型以前未被鉴定为 SARS-CoV-2 感染的抑制剂。进一步的研究鉴定了宿主受体血管紧张素转换酶 2 的变构结合剂；然后，这些化合物被证明可以抑制携带野生型 SARS-CoV-2 以及南非 B.1.351 和英国 B.1.1.7 变体刺突蛋白的假粒子的进入。

更新日期：2021-10-08

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