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Binding Affinities of Factor Xa Inhibitors Estimated by Thermodynamic Integration and MM/GBSA.

Genheden, Samuel LU ; Nilsson, Ingemar and Ryde, Ulf LU (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)
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author
organization
publishing date
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
external identifiers
  • wos:000289710800017
  • pmid:21417269
  • scopus:79955462105
ISSN
1549-960X
DOI
10.1021/ci100458f
language
English
LU publication?
yes
id
51ecd43d-240a-469c-8805-b1ae62065e2e (old id 1883786)
date added to LUP
2011-04-20 08:47:30
date last changed
2017-10-08 03:13:03
@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},
  series       = {Journal of Chemical Information and Modeling},
  title        = {Binding Affinities of Factor Xa Inhibitors Estimated by Thermodynamic Integration and MM/GBSA.},
  url          = {http://dx.doi.org/10.1021/ci100458f},
  volume       = {51},
  year         = {2011},
}