Self-organizing molecular field analysis on pregnane derivatives as human steroidal 5α-reductase inhibitors

Normal growth and development of human prostate is regulated by the androgens which balances cell proliferation and apoptosis. Testosterone (T) and dihydrotestosterone (DHT) are the two key androgens that stimulate most of the androgen action in prostate. Testosterone is converted to DHT by the membrane bound NADPH-dependent 5 alpha-reductase enzyme. As a consequence of the important observation that progesterone and deoxycortisone inhibits the synthesis of DHT by competing with 4-en-3-one function of the testosterone for the 5 alpha-reductase enzyme a number of pregnane derivatives were synthesized and have been reported as inhibitors of human 5 alpha-reductase enzyme. Due to lack of information on the crystal structure of human 5 alpha-reductase, ligand-based 3D-QSAR study has been performed on pregnane derivatives using self-organizing molecular field analysis (SOMFA) for rationalizing the molecular properties and human 5 alpha-reductase inhibitory activities. The statistical results having good cross-validated r(cv)(2) (0.881), non-cross-validated r(2) (0.893) and F-test value (175.527), showed satisfied predictive ability r(pred)(2) (0.777). Analysis of SOMFA models through electrostatic and shape grids provide useful information for the design and optimization of steroidal structure as novel human 5 alpha-reductase inhibitors. (C) 2010 Elsevier Inc. All rights reserved.