Discovery of novel 5 alpha-reductase type II inhibitors by pharmacophore modelling, virtual screening, molecular docking and molecular dynamics simulations

作者：Wang Jhih Lun; Liu Hsuan Liang^*; Zhou Zheng Li; Chen Wei Hsi; Ho Yih

来源：Molecular Simulation, 2015, 41(4): 287-297.

DOI：10.1080/08927022.2013.878865

• benign prostatic hyperplasia
• virtual screening
• molecular dynamics simulations
• 5 alpha-reductase type II
• molecular docking
• pharmacophore

Benign prostatic hyperplasia (BPH) is caused by augmented levels of androgen dihydrotestosterone (DHT) which is involved in the growth of the prostate in humans. 5 alpha-Reductase type II (5 alpha R2) is an intracellular enzyme that catalyses the formation of DHT from testosterone; hence, the inhibition of 5 alpha R2 has emerged as one of the most promising strategies for the treatment of BPH. In this study, a computational approach that integrates ligand-based pharmacophore modelling, virtual screening, molecular docking and molecular dynamics (MD) simulations was adopted to discover novel 5 alpha R2 inhibitors with less side effects. After validating by Fischer's randomisation and Guner-Henry test, the best quantitative pharmacophore model (Hypo1), consisting of two hydrogen-bond acceptors and three hydrophobic features, was subsequently used as a three-dimensional-query in virtual screening to identify potential hits from Maybridge and National Cancer Institute databases. These hits were further filtered by ADMET (absorption, distribution, metabolism, elimination and toxicology) and molecular docking experiments, and their binding stabilities were validated by 10-ns MD simulations. Finally, only one hit was identified as a potential lead based on higher predicted inhibitory activity to 5 alpha R2 compared with the most active inhibitor (finasteride). Our results further suggest that this potential lead could easily be synthesised and has structural novelty, making it a promising candidate for treating BPH.

• 出版日期2015-3-4