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.
Kurunczi
Ludovic
L
University of Medicine and Pharmacy V. Babes, 2 Eftimie Murgu, 300041 Timisoara, Romania. dick@acad-icht.tm.edu.ro
Seclaman
Edward
E
Oprea
Tudor I
TI
Crisan
Luminita
L
Simon
Zeno
Z
D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004958:Estradiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D008954:Models, Biological; D015394:Molecular Structure; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D015203:Reproducibility of Results; D012984:Software
D047628:Estrogen Receptor alpha; D004958:Estradiol