The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
Kinetics of protein–ligand unbinding: Predicting pathways, rates, and rate-limiting steps
Open accessAbstract
Significance: A crucial factor for drug efficacy is not just the binding affinity, but also the mean residence time in the binding pocket, usually quantified by its inverse, k off . This is an important parameter that regulates the time during which the drug is active. Whereas the calculation of the binding affinity is by now routine, the calculation of k off has proven more challenging because the timescales involved far exceed the limits of standard molecular dynamics simulation. We propose a metadynamics-based strategy that allows reaching timescales of seconds, and estimate k off along with unbinding pathways and associated dynamical bottlenecks. The protocol is exemplified for trypsin–benzamidine unbinding. This work is a step towards a more effective computer-based drug design.
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Metadata
- Authors
- Tiwary, P., Limongelli, V., Salvalaglio, M., & Parrinello, M.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2015-01-20
- Volume
- 112
- Issue
- 5
- Pages
- E386-91
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2001357862
- Cited by
- 347
- References
- 57
- FWCI
- 15.95
- Type
- journal article
- Language
- en
- Open access
- green
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