Systematic exploitation of multiple receptor conformations for virtual ligand screening.
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The role of virtual ligand screening in modern drug discovery is to mine large chemical collections and to prioritize for experimental testing a comparatively small and diverse set of compounds with expected activity against a target. Several studies have pointed out that the performance of virtual ligand screening can be improved by taking into account receptor flexibility. Here, we systematically assess how multiple crystallographic receptor conformations, a powerful way of discretely representing protein plasticity, can be exploited in screening protocols to separate binders from non-binders. Our analyses encompass 36 targets of pharmaceutical relevance and are based on actual molecules with reported activity against those targets. The results suggest that an ensemble receptor-based protocol displays a stronger discriminating power between active and inactive molecules as compared to its standard single rigid receptor counterpart. Moreover, such a protocol can be engineered not only to enrich a higher number of active compounds, but also to enhance their chemical diversity. Finally, some clear indications can be gathered on how to select a subset of receptor conformations that is most likely to provide the best performance in a real life scenario.
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Ensemble receptor-based protocols have stronger discriminating power between active and inactive molecules than standard single rigid receptor protocols.
“Overall, ensemble receptor-based protocols display a stronger discriminating power between active and inactive molecules as compared to its standard single rigid receptor counterpart.426”
From Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell (2016) · cites this paper as [426]
Despite many efforts to include protein flexibility in VS experiments, the complex and multifactorial framework of flexible protein-ligand binding is still a great challenge.
“Despite the many efforts made to include the protein flexibility in VS experiments, the complex and multifactorial framework of flexible protein–ligand binding is still a great challenge (Bottegoni et al., 2011; Nunes-Alves and Arantes, 2014; Antunes et al., 2015; Buonfiglio et al., 2015; Kong et al., 2018).”
From Empirical scoring functions for structure-based virtual screening: applications, critical aspects, and challenges (2018) · cites this paper as Bottegoni et al., 2011
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- Authors
- Bottegoni, G., Rocchia, W., Rueda, M., Abagyan, R., & Cavalli, A.
- Affiliations
- Italian Institute of Technology (IT)
- University of California San Diego (US)
- Corresponding author
- Cavalli, Andrea
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-05-17
- Volume
- 6
- Issue
- 5
- Pages
- e18845
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3098722
- OpenAlex
- W2075802963
- Cited by
- 96
- References
- 65
- Citations by year
- 2026: 3 · 2025: 2 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 7 · 2020: 6 · 2019: 3 · 2018: 6 · 2017: 9 · 2016: 6 · 2015: 9 · 2014: 7 · 2013: 10 · 2012: 14
- FWCI
- 9.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- CINECA IRIS Institutional Research information system (University of Urbino) (submittedVersion)
- Funders
- Istituto Italiano di Tecnologia
- National Institute of General Medical Sciences (R01GM071872)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- virtual ligand screening, receptor flexibility, protein plasticity, target-based drug discovery
- MeSH terms
- Algorithms, Humans, Ligands, Protein Binding, Protein Conformation, Receptors, Cell Surface, Drug Design, Combinatorial Chemistry Techniques
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