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

Jhih Lun Wang, Hsuan Liang Liu, Zheng Li Zhou, Wei Hsi Chen, Yih Ho

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Benign prostatic hyperplasia (BPH) is caused by augmented levels of androgen dihydrotestosterone (DHT) which is involved in the growth of the prostate in humans. 5α-Reductase type II (5αR2) is an intracellular enzyme that catalyses the formation of DHT from testosterone; hence, the inhibition of 5αR2 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 5αR2 inhibitors with less side effects. After validating by Fischer's randomisation and Güner-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 5αR2 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.

Original languageEnglish
Pages (from-to)287-297
Number of pages11
JournalMolecular Simulation
Volume41
Issue number4
DOIs
Publication statusPublished - Mar 4 2015

Fingerprint

Molecular Docking
Virtual Screening
Dihydrotestosterone
Hits
inhibitors
Molecular Dynamics Simulation
Inhibitor
Molecular dynamics
Screening
Oxidoreductases
screening
Lead
molecular dynamics
Finasteride
Computer simulation
Modeling
Metabolism
toxicology
Androgens
Toxicology

Keywords

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

ASJC Scopus subject areas

  • Condensed Matter Physics
  • Modelling and Simulation
  • Chemistry(all)
  • Chemical Engineering(all)
  • Materials Science(all)
  • Information Systems

Cite this

Discovery of novel 5α-reductase type II inhibitors by pharmacophore modelling, virtual screening, molecular docking and molecular dynamics simulations. / Wang, Jhih Lun; Liu, Hsuan Liang; Zhou, Zheng Li; Chen, Wei Hsi; Ho, Yih.

In: Molecular Simulation, Vol. 41, No. 4, 04.03.2015, p. 287-297.

Research output: Contribution to journalArticle

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