ArticleACS pharmacology & translational science2021
A Blueprint for High Affinity SARS-CoV-2 Mpro Inhibitors from Activity-Based Compound Library Screening Guided by Analysis of Protein Dynamics.
Article in ACS pharmacology & translational science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 65 citations in OpenAlex.
- Two faces of drug repurposing data in machine learning-driven structure-based virtual screening supported by interaction fingerprints.Journal of computer-aided molecular design · 2026Article
- Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 MScientific reports · 2025Article
- SARS-CoV-2 Mpro Dihedral Angles Reveal Allosteric Signaling.Proteins · 2025Article
- Macromolecular crystallography at Elettra: current and future perspectives.Journal of synchrotron radiation · 2025Article
- Virtual Screening Identifies Inhibitors of SARS-CoV-2 Main Protease through Pharmacophore and Similarity Approaches.Current pharmaceutical design · 2025Article
- ClickGen: Directed exploration of synthesizable chemical space via modular reactions and reinforcement learning.Nature communications · 2024Article
- SARS-CoV-2 3CLPro Dihedral Angles Reveal Allosteric Signaling.bioRxiv : the preprint server for biology · 2024Article
- Consensus Pharmacophore Strategy For Identifying Novel SARS-Cov-2 MJournal of chemical information and modeling · 2024Article
- Unexpected Single-Ligand Occupancy and Negative Cooperativity in the SARS-CoV-2 Main Protease.Journal of chemical information and modeling · 2024Article
- Combining virtual screening with cis-/trans-cleavage enzymatic assays effectively reveals broad-spectrum inhibitors that target the main proteases of SARS-CoV-2 and MERS-CoV.Antiviral research · 2023Article
- Antitarget, Anti-SARS-CoV-2 Leads, Drugs, and the Drug Discovery-Genetics Alliance Perspective.Journal of medicinal chemistry · 2023Review
- Lessons Learnt from COVID-19: Computational Strategies for Facing Present and Future Pandemics.International journal of molecular sciences · 2023Review
- Elettra-Sincrotrone Trieste: present and future.European physical journal plus · 2023Article
- Rational design of the zonulin inhibitor AT1001 derivatives as potential anti SARS-CoV-2.European journal of medicinal chemistry · 2022Article
- In Silico Methods for Identification of Potential Active Sites of Therapeutic Targets.Molecules (Basel, Switzerland) · 2022Review
- Targeting SARS-CoV-2 Main Protease for Treatment of COVID-19: Covalent Inhibitors Structure-Activity Relationship Insights and Evolution Perspectives.Journal of medicinal chemistry · 2022Review
- Exscalate4CoV: Innovative High Performing Computing (HPC) Strategies to Tackle Pandemic Crisis.International journal of molecular sciences · 2022Article
- A Self-Immolative Fluorescent Probe for Selective Detection of SARS-CoV-2 Main Protease.Analytical chemistry · 2022Article
- Pre-exascale HPC approaches for molecular dynamics simulations. Covid-19 research: A use case.Wiley interdisciplinary reviews. Computational molecular science · 2022Article
- Fast and Effective Prediction of the Absolute Binding Free Energies of Covalent Inhibitors of SARS-CoV-2 Main Protease and 20S Proteasome.Journal of the American Chemical Society · 2022Article
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Authors and funding
20 authors at 10 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The SARS-CoV-2 coronavirus outbreak continues to spread at a rapid rate worldwide. The main protease (Mpro) is an attractive target for anti-COVID-19 agents. Unexpected difficulties have been encountered in the design of specific inhibitors. Here, by analyzing an ensemble of ∼30 000 SARS-CoV-2 Mpro conformations from crystallographic studies and molecular simulations, we show that small structural variations in the binding site dramatically impact ligand binding properties. Hence, traditional druggability indices fail to adequately discriminate between highly and poorly druggable conformations of the binding site. By performing ∼200 virtual screenings of compound libraries on selected protein structures, we redefine the protein's druggability as the consensus chemical space arising from the multiple conformations of the binding site formed upon ligand binding. This procedure revealed a unique SARS-CoV-2 Mpro blueprint that led to a definition of a specific structure-based pharmacophore. The latter explains the poor transferability of potent SARS-CoV Mpro inhibitors to SARS-CoV-2 Mpro, despite the identical sequences of the active sites. Importantly, application of the pharmacophore predicted novel high affinity inhibitors of SARS-CoV-2 Mpro, that were validated by
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