Title

Novel aromatase inhibitors selection using induced fit docking and extra precision methods: Potential clinical use in ER-alpha-positive breast cancer

Authors

Ranjith Kumavath1*, Manan Azad1, Pratap Devarapalli1, Sandeep Tiwari3, Shreya Kar4, Debmalya Barh2, Vasco Azevedo3 & Alan Prem Kumar4-8

Affiliation

1Department of Genomic Science, School of Biological Sciences,Central University of Kerala, Padannakad P.O., Kasaragod-671314, Kerala, India; 2Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri-721172, PurbaMedinipur, West Bengal, India; 3Instituto de CiênciasBiológicas, Universidade Federal de Minas Gerais. MG, Brazil; 4Cancer Science Institute of Singapore, National University of Singapore, Singapore-117599; 5National University Cancer Institute, National University Health System, Singapore-119074; 6Department of Biological Sciences, University of North Texas, Denton-762035017, Texas, USA; 7Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore-117600; 8Faculty of Health Sciences, School of Biomedical Sciences, Curtin University, Bently, Western Australia-6102

Email

Dr. Ranjith Kumavath - Email: rnkumavath@gmail.com; RNKumavath@cukerala.edu.in; Phone: 0091-8547648620; Fax: 0467-2282250; Dr. Alan Prem Kuma - Email: csiapk@nus.edu.sg; *Corresponding author

Article Type

Hypothesis

Date

Received April 5, 2016; Revised May 25, 2016; Accepted August 12, 2016; Published October 10, 2016

Aromatase (CYP19A1) the key enzyme of estrogen biosynthesis, is often deregulated in breast cancer patients. It catalyzes the conversion of androgen to estrogen, thus responsible for production of estrogen in human body. However, it causes over-production of estrogen which eventually leads to proliferation of breast cancer cells. Identification of new small molecule inhibitors targeted against CYP19A1 therefore, facilitates to increase drug sensitivity of cancer cells. In this scenario, the present study aims to identify new molecules which could block or suppress the activity of aromatase enzyme by molecular docking studies using Schrödinger-Maestro v9.3. In this study we used in silico approach by modeling CYP19A1 protein the strcture was subjected to protein preparation wizard; to add hydrogen and optimize the protonation states of Thr310 and Ser478 and Asp309 residues. Active site of the CYP19A1 protein was identified using SiteMap tool of Scchrodinger package. We further carried out docking studies by means of Glid, with various ligands. Based on glid score, potential ligands were screeened and their interaction with CYP19A1 was identified. The best hits were further screened for Lipinski’s rule for drug-likeliness and bioactivity scoring properties. Thus, we report two rubivivaxin and rhodethrin compounds that have successfully satisfied all in silico parameters, necessitating further in vitro and in vivo studies.

Keywords

aromatase inhibitors, anticancer drug, breast cancer, molecular docking

Citation

Kumavath et al. Bioinformation 12(6): 324-331 (2016)

Edited by

P Kangueane

ISSN

0973-2063

Publisher

Biomedical Informatics

License

This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.