Binding Affinities of Factor Xa Inhibitors Estimated by Thermodynamic Integration and MM/GBSA.
(2011) In Journal of Chemical Information and Modeling 51(Online March 18, 2011). p.947-958- Abstract
- We present free energy estimates of nine 3-amidinobenzyl-1H-indole-2-carboxamide inhibitors of factor Xa. Using alchemical thermodynamic integration (TI) calculations, we estimate the difference in binding free energies with high accuracy and precision, except for mutations involving one of the amidinobenzyl rings. Crystal studies show that the inhibitors may bind in two distinct conformations, and using TI, we show that the two conformations give a similar binding affinity. Furthermore, we show that we can reduce the computational demand, while still retaining a high accuracy and precision, by using fewer integration points and shorter protein-ligand simulations. Finally, we have compared the TI results to those obtained with the simpler... (More)
- We present free energy estimates of nine 3-amidinobenzyl-1H-indole-2-carboxamide inhibitors of factor Xa. Using alchemical thermodynamic integration (TI) calculations, we estimate the difference in binding free energies with high accuracy and precision, except for mutations involving one of the amidinobenzyl rings. Crystal studies show that the inhibitors may bind in two distinct conformations, and using TI, we show that the two conformations give a similar binding affinity. Furthermore, we show that we can reduce the computational demand, while still retaining a high accuracy and precision, by using fewer integration points and shorter protein-ligand simulations. Finally, we have compared the TI results to those obtained with the simpler MM/GBSA method (molecular-mechanics with generalized Born surface-area solvation). MM/GBSA gives better results for the mutations that involve a change of net charge, but if a precision similar to that of the TI method is required, the MM/GBSA method is actually slightly more expensive. Thus, we have shown that TI could be a valuable tool in drug design. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1883786
- author
- Genheden, Samuel LU ; Nilsson, Ingemar and Ryde, Ulf LU
- organization
- publishing date
- 2011
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Chemical Information and Modeling
- volume
- 51
- issue
- Online March 18, 2011
- pages
- 947 - 958
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- wos:000289710800017
- pmid:21417269
- scopus:79955462105
- pmid:21417269
- ISSN
- 1549-960X
- DOI
- 10.1021/ci100458f
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Theoretical Chemistry (S) (011001039)
- id
- 51ecd43d-240a-469c-8805-b1ae62065e2e (old id 1883786)
- date added to LUP
- 2016-04-01 10:32:17
- date last changed
- 2023-02-11 21:06:27
@article{51ecd43d-240a-469c-8805-b1ae62065e2e, abstract = {{We present free energy estimates of nine 3-amidinobenzyl-1H-indole-2-carboxamide inhibitors of factor Xa. Using alchemical thermodynamic integration (TI) calculations, we estimate the difference in binding free energies with high accuracy and precision, except for mutations involving one of the amidinobenzyl rings. Crystal studies show that the inhibitors may bind in two distinct conformations, and using TI, we show that the two conformations give a similar binding affinity. Furthermore, we show that we can reduce the computational demand, while still retaining a high accuracy and precision, by using fewer integration points and shorter protein-ligand simulations. Finally, we have compared the TI results to those obtained with the simpler MM/GBSA method (molecular-mechanics with generalized Born surface-area solvation). MM/GBSA gives better results for the mutations that involve a change of net charge, but if a precision similar to that of the TI method is required, the MM/GBSA method is actually slightly more expensive. Thus, we have shown that TI could be a valuable tool in drug design.}}, author = {{Genheden, Samuel and Nilsson, Ingemar and Ryde, Ulf}}, issn = {{1549-960X}}, language = {{eng}}, number = {{Online March 18, 2011}}, pages = {{947--958}}, publisher = {{The American Chemical Society (ACS)}}, series = {{Journal of Chemical Information and Modeling}}, title = {{Binding Affinities of Factor Xa Inhibitors Estimated by Thermodynamic Integration and MM/GBSA.}}, url = {{https://lup.lub.lu.se/search/files/136742536/153_fxa.pdf}}, doi = {{10.1021/ci100458f}}, volume = {{51}}, year = {{2011}}, }