Binding affinities of the farnesoid X receptor in the D3R Grand Challenge 2 estimated by free-energy perturbation and docking

摘要

AbstractWe have studied the binding of 102 ligands to the farnesoid X receptor within the D3R Grand Challenge 2016 blind-prediction competition. First, we employed docking with five different docking software and scoring functions. The selected docked poses gave an average root-mean-squared deviation of 4.2??. Consensus scoring gave decent results with a Kendall’s τ of 0.26?±?0.06 and a Spearman’s ρ of 0.41?±?0.08. For a subset of 33 ligands, we calculated relative binding free energies with free-energy perturbation. Five transformations between the ligands involved a change of the net charge and we implemented and benchmarked a semi-analytic correction (Rocklin et al., J Chem Phys 139:184103, 2013) for artifacts caused by the periodic boundary conditions and Ewald summation. The results gave a mean absolute deviation of 7.5?kJ/mol compared to the experimental estimates and a correlation coefficient ofR2?=?0.1. These results were among the four best in this competition out of 22 submissions. The charge corrections were significant (7–8?kJ/mol) and always improved the results. By employing 23 intermediate states in the free-energy perturbation, there was a proper overlap between all states and the precision was 0.1–0.7?kJ/mol. However, thermodynamic cycles indicate that the sampling was insufficient in some of the perturbations.]]>