title: Binding affinities of factor Xa inhibitors estimated by thermodynamic integration and MM/GBSA.
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.
authors.affiliation: Department of Theoretical Chemistry, Lund University , Chemical Centre, P.O. Box 124, SE-221 00 Lund, Sweden.
authors.forename: Samuel
authors.initials: S
authors.lastname: Genheden
authors.forename: Ingemar
authors.initials: I
authors.lastname: Nilsson
authors.forename: Ulf
authors.initials: U
authors.lastname: Ryde
mesh_terms: D000465:Algorithms; D000577:Amides / Q000737:chemistry; D000578:Amidines / Q000737:chemistry; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D007211:Indoles / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D000577:Amides; D000578:Amidines; D065427:Factor Xa Inhibitors; D007211:Indoles; D008024:Ligands; D015842:Serine Proteinase Inhibitors; D015951:Factor Xa