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

Samuel Genheden, Ingemar Nilsson, Ulf Ryde

Research output: Contribution to journalArticlepeer-review

60 Citations (SciVal)
158 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)947-958
JournalJournal of Chemical Information and Modeling
Volume51
Issue numberOnline March 18, 2011
DOIs
Publication statusPublished - 2011

Bibliographical note

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)

Subject classification (UKÄ)

  • Theoretical Chemistry

Fingerprint

Dive into the research topics of 'Binding Affinities of Factor Xa Inhibitors Estimated by Thermodynamic Integration and MM/GBSA.'. Together they form a unique fingerprint.

Cite this