MTD-PLS: a PLS variant of the minimal topologic difference method. III. Mapping interactions between estradiol derivatives and the alpha estrogenic receptor

A homogeneous collection of 45 estrogen agonist derivatives with relative binding affinities measured to the estrogen receptor from Ratus norvegicus was used. The quantitative structure-activity relationships were derived using an improved minimal topologic difference (MTD) method in a partial least-squares (PLS) variant. The spatially assigned analysis of fragment properties can provide receptor site maps, within the limits of the existing series. A steric misfit was found for the steroidal position 2; benefic hydrophobic and van der Waals (enhanced by high polarizability) interactions were found for the 17alpha-CH=CH-X group. MTD-PLS mapping results are confirmed by the experimentally derived estradiol-estrogen receptor binding site contacts (based on X-ray crystallography). Our results suggest that this MTD-PLS method can yield useful results for interactions with receptors of unknown 3D structure and, generally, for the steric rigidity of receptor sites.