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 17β-estradiol were available in both isoforms of the nuclear estrogen receptor (ERα, ERβ) 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 ERα and ERβ utilizing the docking program Gold. The binding energy (ΔE) 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 ERα, but performed poorly in ERβ. 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 ΔE calculated in solution proved particularly predictive for the estrogen-like ligands in ERβ. Finally the estrogen subtype selective nature RBA (ERα/ERβ) 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 (ERα/ERβ), illustrating the utility of this method as a prescreening tool in the development of novel estrogen receptor subtype selective ligands.