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Hybrid In Silico Approach Reveals Novel Inhibitors of Multiple SARS-CoV-2 Variants.
Jain, Sankalp; Talley, Daniel C; Baljinnyam, Bolormaa; Choe, Jun; Hanson, Quinlin; Zhu, Wei; Xu, Miao; Chen, Catherine Z; Zheng, Wei; Hu, Xin; Shen, Min; Rai, Ganesha; Hall, Matthew D; Simeonov, Anton; Zakharov, Alexey V.
  • Jain S; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Talley DC; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Baljinnyam B; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Choe J; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Hanson Q; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Zhu W; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Xu M; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Chen CZ; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Zheng W; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Hu X; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Shen M; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Rai G; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Hall MD; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Simeonov A; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
  • Zakharov AV; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.
ACS Pharmacol Transl Sci ; 4(5): 1675-1688, 2021 Oct 08.
Article in English | MEDLINE | ID: covidwho-1450269
Preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
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ABSTRACT
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.

Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study / Systematic review/Meta Analysis Topics: Variants Language: English Journal: ACS Pharmacol Transl Sci Year: 2021 Document Type: Article Affiliation country: Acsptsci.1c00176

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study / Systematic review/Meta Analysis Topics: Variants Language: English Journal: ACS Pharmacol Transl Sci Year: 2021 Document Type: Article Affiliation country: Acsptsci.1c00176