Extracting binding energies and binding modes from biomolecular simulations of fragment binding to endothiapepsin
Abstract: Fragment‐based drug discovery (FBDD) aims to discover a set of small binding fragments that may be subsequently linked together. Therefore, in‐depth knowledge of the individual fragments' structural and energetic binding properties is essential. In addition to experimental techniques, the direct simulation of fragment binding by molecular dynamics (MD) simulations became popular to characterize fragment binding. However, former studies showed that long simulation times and high computational demands per fragment are needed, which limits applicability in FBDD. Here, we performed short, unbiased MD simulations of direct fragment binding to endothiapepsin, a well‐characterized model system of pepsin‐like aspartic proteases. To evaluate the strengths and limitations of short MD simulations for the structural and energetic characterization of fragment binding, we predicted the fragments' absolute free energies and binding poses based on the direct simulations of fragment binding and compared the predictions to experimental data. The predicted absolute free energies are in fair agreement with the experiment. Combining the MD data with binding mode predictions from molecular docking approaches helped to correctly identify the most promising fragments for further chemical optimization. Importantly, all computations and predictions were done within 5 days, suggesting that MD simulations may become a viable tool in FBDD projects.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Extracting binding energies and binding modes from biomolecular simulations of fragment binding to endothiapepsin ; day:06 ; month:02 ; year:2024 ; extent:17
Archiv der Pharmazie ; (06.02.2024) (gesamt 17)
- Creator
- DOI
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10.1002/ardp.202300612
- URN
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urn:nbn:de:101:1-2024020714272911491101
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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15.08.2025, 7:30 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Schmitz, Birte
- Frieg, Benedikt
- Homeyer, Nadine
- Jessen, Gisela
- Gohlke, Holger
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Biomolecular force fields probed by free energies of binding and solvation
Excitonic binding energies in quantum wells
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Quantifying Biomolecular Binding Constants using Video Paper Analytical Devices
Non-abelian binding energies from the lightcone bootstrap
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Excitonic binding energies in quantum wells
Self-binding energies in AdS
Quantification of biomolecular binding dynamics by Fluorescence Correlation Spectroscopy
Quantifying Biomolecular Binding Constants using Video Paper Analytical Devices
Non-abelian binding energies from the lightcone bootstrap
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