This title appears in the Scientific Report :
2024
Please use the identifier:
http://dx.doi.org/10.34734/FZJ-2024-03033 in citations.
Please use the identifier: http://dx.doi.org/10.1002/ardp.202300612 in citations.
Extracting binding energies and binding modes from biomolecular simulations of fragment binding to endothiapepsin
Extracting binding energies and binding modes from biomolecular simulations of fragment binding to endothiapepsin
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 direc...
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Personal Name(s): | Schmitz, Birte |
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Frieg, Benedikt / Homeyer, Nadine / Jessen, Gisela / Gohlke, Holger (Corresponding author) | |
Contributing Institute: |
Strukturbiochemie; IBI-7 John von Neumann - Institut für Computing; NIC Jülich Supercomputing Center; JSC Bioinformatik; IBG-4 |
Published in: | Archiv der Pharmazie, 357 (2024) 5, S. e2300612 |
Imprint: |
Weinheim
Wiley-VCH
2024
|
DOI: |
10.34734/FZJ-2024-03033 |
DOI: |
10.1002/ardp.202300612 |
Document Type: |
Journal Article |
Research Program: |
GRK 2158: Naturstoffe und Analoga gegen Therapie-resistente Tumoren und Mikroorganismen: Neue Leitstrukturen und Wirkmechanismen Biological and environmental resources for sustainable use Domain-Specific Simulation & Data Life Cycle Labs (SDLs) and Research Groups |
Link: |
OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://dx.doi.org/10.1002/ardp.202300612 in citations.
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. |