Journal Article

Biological activity-based modeling identifies antiviral leads against SARS-CoV-2

Lee, Emily M., Huang, Wenwei, Simeonov, Anton, Lo, Donald, Xu, Miao, Zhu, Hu, Zhang, Li, Tang, Hengli, Austin, Christopher P., Hall, Mathew D., Zhao, Jinghua, Chen, Catherine Z., Shamim, Khalida, Zhu, Wei, Zheng, Wei, Qiu, Xiangguo, Bougie, Danielle, Huang, Ruili, Xia, Menghang, He, Shihua

2021

Overview

Computational approaches for drug discovery, such as quantitative structure–activity relationship, rely on structural similarities of small molecules to infer biological activity but are often limited to identifying new drug candidates in the chemical spaces close to known ligands. Here we report a biological activity-based modeling (BABM) approach, in which compound activity profiles established across multiple assays are used as signatures to predict compound activity in other assays or against a new target. This approach was validated by identifying candidate antivirals for Zika and Ebola viruses based on high-throughput screening data. BABM models were then applied to predict 311 compounds with potential activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the predicted compounds, 32% had antiviral activity in a cell culture live virus assay, the most potent compounds showing a half-maximal inhibitory concentration in the nanomolar range. Most of the confirmed anti-SARS-CoV-2 compounds were found to be viral entry inhibitors and/or autophagy modulators. The confirmed compounds have the potential to be further developed into anti-SARS-CoV-2 therapies. Activity profiles generated from quantitative high-throughput screening improve drug candidate prediction.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/114/2397 / 631/154/1435/2163 / 631/154/1435/2418 / Agriculture / Antiviral activity / Antiviral agents / Antiviral Agents - pharmacology / Antiviral drugs / Assaying / Autophagy / Bioinformatics / Biological activity / Biomedical and Life Sciences / Biomedical Engineering/Biotechnology / Biomedicine / Biotechnology / Cell culture / Computer applications / Coronaviruses / COVID-19 / COVID-19 - genetics / COVID-19 - virology / COVID-19 Drug Treatment / Dosage and administration / Drug development / Drug Discovery - methods / Drug Evaluation, Preclinical - methods / High-throughput screening / High-Throughput Screening Assays - methods / Humans / Life Sciences / Modulators / Phagocytosis / SARS-CoV-2 - drug effects / SARS-CoV-2 - pathogenicity / Screening / Severe acute respiratory syndrome coronavirus 2 / Vector-borne diseases / Viral diseases / Viruses