Abstract.
Quantitative Structure-Activity Relationship (QSAR) study of two sets of oral progestogens was carried out by using Principal Component Analysis (PCA), Hierarchical Cluster Analysis (HCA) and Partial Least Squares (PLS). A priori, computed (at DFT 6-31G** level) and molecular graphics and modeling descriptors were employed. Molecular graphics and modeling studies of crystal structures of complexes progesterone receptor (PR)-progesterone, Fab'-progesterone and PR-metribolone have been performed. QSAR of progestogens is a three-dimensional phenomenon (over 96% of information is explained by the first three Principal Components), which can be, although it exhibits significant non-linearity, treated well with linear methods such as PLS. Progestogen activity depends primarily on double bond contents and resonance effects which define the skeletal conformation, and also on substituent characteristics (size, conformational and electronic properties). Sterical relationships between a substituent at C6(sp²) or C6(sp³)-a and sulfur atom from Met801 residue of PR are important for progesterone binding to the protein and can be quantified. Basically the same was observed for substituents at b-C10 with respect to residue Met759.

Keywords.
Progesterone; Chemometrics; Principal Component Analysis; Hierarchical Cluster Analysis; Partial Least Squares.

Keywords Plus.