title: Predicting binding modes from free energy calculations.
abstract: To produce reliable predictions of bioactive conformations is a major challenge in the field of structure-based inhibitor design and is a requirement for accurate binding free energy predictions with structure-based methods. A series of HIV-1 reverse transcriptase inhibitors was cross-docked using a non-native crystal structure that resulted in two distinct clusters of possible conformations. One of these clusters was compatible with an existing crystal structure, whereas the other displayed a flipped heterocyclic group. Binding free energies, using the non-native crystal structure, calculated from several scoring functions, were similar for the two clusters, and no conclusion about the binding mode could be drawn from these results. The two clusters could be separated through rescoring with the linear interaction method (LIE) in combination with molecular dynamics simulations, which leads to a binding mode prediction in line with experimental crystallographic data. Further, the LIE model produces the best correlation between experimental and calculated binding free energies among the tested scoring methods.
authors.affiliation: Department of Cell and Molecular Biology, Uppsala University, Box 596, SE-751 24 Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Nervall
authors.forename: Peter
authors.initials: P
authors.lastname: Hanspers
authors.forename: Jens
authors.initials: J
authors.lastname: Carlsson
authors.forename: Lars
authors.initials: L
authors.lastname: Boukharta
authors.forename: Johan
authors.initials: J
authors.lastname: Aqvist
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase