Molecular Modeling on Structure-Function Analysis of Human Progesterone Receptor Modulators

Considering the significance of progesterone receptor (PR) modulators, the present study is explored to envisage the biophoric signals for binding to selective PR subtype-A using ligand-based quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies on nonsteroidal substituted quinoline and cyclocymopol monomethyl ether derivatives. Consensus QSAR models (Training set (Tr): n_Tr=100, R²_pred=0.702; test set (Ts): n_Ts=30, R²_pred=0.705, R²_m=0.635; validation set (Vs): n_Vs=40, R²_pred=0.715, R²_m=0.680) suggest that molecular topology, atomic polarizability and electronegativity, atomic mass and van der Waals volume of the ligands have influence on the presence of functional atoms (F, Cl, N and O) and consequently contribute significant relations on ligand binding affinity. Receptor independent space modeling study (Tr: n_Tr=26, Q²=0.927; Ts: n_Ts=60, R²_pred=0.613, R²_m=0.545; Vs: n_Vs=84, R²_pred=0.611, R²_m=0.507) indicates the importance of aromatic ring, hydrogen bond donor, molecular hydrophobicity and steric influence for receptor binding. The structure-function characterization is adjudged with the receptor-based docking study, explaining the significance of the mapped molecular attributes for ligand-receptor interaction in the catalytic cleft of PR-A.