Simulations and active learning enable efficient identification of an experimentally-validated broad coronavirus inhibitor

Katarina Elez, Tim Hempel, Jonathan H. Shrimp, Nicole Moor, Lluís Raich, Cheila Rocha, Robin Winter, Tuan Le, Stefan Pöhlmann, Markus Hoffmann, Matthew D. Hall and Frank Noé ()
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Katarina Elez: Freie Universität Berlin
Tim Hempel: Freie Universität Berlin
Jonathan H. Shrimp: National Institutes of Health
Nicole Moor: German Primate Center - Leibniz Institute for Primate Research
Lluís Raich: Freie Universität Berlin
Cheila Rocha: German Primate Center - Leibniz Institute for Primate Research
Robin Winter: Freie Universität Berlin
Tuan Le: Freie Universität Berlin
Stefan Pöhlmann: German Primate Center - Leibniz Institute for Primate Research
Markus Hoffmann: German Primate Center - Leibniz Institute for Primate Research
Matthew D. Hall: National Institutes of Health
Frank Noé: Freie Universität Berlin

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Drug screening resembles finding a needle in a haystack: identifying a few effective inhibitors from a large pool of potential drugs. Large experimental screens are expensive and time-consuming, while virtual screening trades off computational efficiency and experimental correlation. Here we develop a framework that combines molecular dynamics (MD) simulations with active learning. Two components drastically reduce the number of candidates needing experimental testing to less than 20: (1) a target-specific score that evaluates target inhibition and (2) extensive MD simulations to generate a receptor ensemble. The active learning approach reduces the number of compounds requiring experimental testing to less than 10 and cuts computational costs by ∼29-fold. Using this framework, we discovered BMS-262084 as a potent inhibitor of TMPRSS2 (IC50 = 1.82 nM). Cell-based experiments confirmed BMS-262084’s efficacy in blocking entry of various SARS-CoV-2 variants and other coronaviruses. The identified inhibitor holds promise for treating viral and other diseases involving TMPRSS2.

Date: 2025
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DOI: 10.1038/s41467-025-62139-5

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