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Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects
Open accessPublished version of a preprint
Abstract
Accurate ranking of compounds with regards to their binding affinity to a protein using computational methods is of great interest to pharmaceutical research. Physics-based free energy calculations are regarded as the most rigorous way to estimate binding affinity. In recent years, many retrospective studies carried out both in academia and industry have demonstrated its potential. Here, we present the results of large-scale prospective application of the FEP+ method in active drug discovery projects in an industry setting at Merck KGaA, Darmstadt, Germany. We compare these prospective data to results obtained on a new diverse, public benchmark of eight pharmaceutically relevant targets. Our results offer insights into the challenges faced when using free energy calculations in real-life drug discovery projects and identify limitations that could be tackled by future method development. The new public data set we provide to the community can support further method development and comparative benchmarking of free energy calculations.
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The maximal and current accuracy of rigorous protein-ligand binding free energy calculations
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Quantitatively accounting for protein reorganization in computer-aided drug design
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Metadata
- Authors
- Schindler, C. E. M., Baumann, H., Blum, A., Böse, D., Buchstaller, H.-P., Burgdorf, L., Cappel, D., Chekler, E., Czodrowski, P., Dorsch, D., Eguida, M. K. I., Follows, B., Fuchß, T., Grädler, U., Gunera, J., Johnson, T., Jorand Lebrun, C., Karra, S., Klein, M., Knehans, T., Koetzner, L., Krier, M., Leiendecker, M., Leuthner, B., Li, L., Mochalkin, I., Musil, D., Neagu, C., Rippmann, F., Schiemann, K., Schulz, R., Steinbrecher, T., Tanzer, E.-M., Unzue Lopez, A., Viacava Follis, A., Wegener, A., & Kuhn, D.
- Venue
- Journal of Chemical Information and Modeling
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-08-19
- Volume
- 60
- Issue
- 11
- Pages
- 5457-5474
- ISSN
- 1549-9596 (ISSN-L)
- 1549-960X
- OpenAlex
- W3054319032
- Cited by
- 303
- References
- 90
- FWCI
- 17.75
- Type
- journal article
- Language
- en
- Open access
- green
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- Schindler, C. E. M., Baumann, H., Blum, A., Böse, D., Buchstaller, H.-P., Burgdorf, L., Cappel, D., Chekler, E., Czodrowski, P., Dorsch, D., Eguida, M. K. I., Follows, B., Fuchß, T., Grädler, U., Gunera, J., Johnson, T., Jorand Lebrun, C., Karra, S., Klein, M., . . . Kuhn, D. (2020). Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects. Journal of Chemical Information and Modeling. https://doi.org/10.1021/acs.jcim.0c00900
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
