Use of binding energy in comparative molecular field analysis of isoform selective estrogen receptor ligands

A diverse set of 30 estrogen receptor ligands whose relative binding affinities (RBA) with respect to 17beta-estradiol were available in both isoforms of the nuclear estrogen receptor (ERalpha, ERbeta) were studied with a combination of comparative molecular field analysis (CoMFA) and binding energy calculations. The ligands were docked inside the ligand-binding domain (LBD) of both ERalpha and ERbeta utilizing the docking program Gold. The binding energy (DeltaE) and corresponding non-bonded interactions (NB) of the subsequent protein-ligand complexes were calculated in both the gas-phase and implicit aqueous solution using the generalized born surface area (GB/SA) model. A partial least-squares analysis of the calculated energies indicated that the NB(g) were sufficiently predictive in ERalpha, but performed poorly in ERbeta. Further analysis of the calculated energies by dissecting the ligands into two distinct classes, estrogen-like and heterocyclic, yielded more predictive models. In particular the DeltaE calculated in solution proved particularly predictive for the estrogen-like ligands in ERbeta. Finally the estrogen subtype selective nature RBA (ERalpha/ERbeta) of a test-set consisting of six of the original ligands was predicted. The combined CoMFA and non-bonded interaction energy model ranked correctly the ligands in order of increasing RBA (ERalpha/ERbeta), illustrating the utility of this method as a prescreening tool in the development of novel estrogen receptor subtype selective ligands.