Hands-off linear interaction energy approach to binding mode and affinity estimation of estrogens.
With this work we target the development of a predictictive model for the identification of small molecules which bind to the estrogen receptor alpha and, thus, may act as endocrine disruptors. We propose a combined thermodynamic approach for the estimation of preferential binding modes along with corresponding free energy differences using a linear interaction energy (LIE) ansatz. The LIE model is extended by a Monte Carlo approach for the computation of conformational entropies as recently developed by our group. Incorporating the entropy contribution substantially increased the correlation with experimental affinity values. Both squared coefficients for the fitted data as well as the more meaningful leave-one-out cross-validation of predicted energies were elevated up to r(Fit)² = 0.87 and q(LOO)² = 0.82, respectively. All calculations have been performed on a set of 31 highly diverse ligands regarding their structural properties and affinities to the estrogen receptor alpha. Comparison of predicted ligand orientations with crystallographic data retrieved from the Protein database pdb.org revealed remarkable binding mode predictions.
Department of Numerical Analysis and Modelling, ZIB Zuse Institute Berlin , 14195 Berlin, Germany.
Vedat
V
Durmaz
Sebastian
S
Schmidt
Peggy
P
Sabri
Christian
C
Piechotta
Marcus
M
Weber
D001559:Benzhydryl Compounds / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D004958:Estradiol / Q000737:chemistry*; D047628:Estrogen Receptor alpha / Q000737:chemistry*; D019833:Genistein / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D009010:Monte Carlo Method; D010636:Phenols / Q000737:chemistry*; D011485:Protein Binding; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000737:chemistry; D013816:Thermodynamics; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D004958:Estradiol; D047628:Estrogen Receptor alpha; D019833:Genistein; D008024:Ligands; D010636:Phenols; D013629:Tamoxifen; C506487:ESR1 protein, human; C016601:afimoxifene; C006780:bisphenol A; D000098826:Bisphenol A Compounds