title: Novel aromatase inhibitors selection using induced fit docking and extra precision methods: Potential clinical use in ER-alpha-positive breast cancer.
abstract: 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.
authors.affiliation: Department of Genomic Science, School of Biological Sciences,Central University of Kerala, Padannakad P.O., Kasaragod-671314, Kerala, India.
authors.forename: Ranjith
authors.initials: R
authors.lastname: Kumavath
authors.affiliation: Department of Genomic Science, School of Biological Sciences,Central University of Kerala, Padannakad P.O., Kasaragod-671314, Kerala, India.
authors.forename: Manan
authors.initials: M
authors.lastname: Azad
authors.affiliation: Department of Genomic Science, School of Biological Sciences,Central University of Kerala, Padannakad P.O., Kasaragod-671314, Kerala, India.
authors.forename: Pratap
authors.initials: P
authors.lastname: Devarapalli
authors.affiliation: Instituto de CiênciasBiológicas, Universidade Federal de Minas Gerais. MG,Brazil.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Tiwari
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore-117599.
authors.forename: Shreya
authors.initials: S
authors.lastname: Kar
authors.affiliation: Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri-721172, PurbaMedinipur, West Bengal, India.
authors.forename: Debmalya
authors.initials: D
authors.lastname: Barh
authors.affiliation: Instituto de CiênciasBiológicas, Universidade Federal de Minas Gerais. MG,Brazil.
authors.forename: Vasco
authors.initials: V
authors.lastname: Azevedo
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore-117599; National University Cancer Institute, National University Health System, Singapore-119074; Department of Biological Sciences, University of North Texas, Denton-762035017, Texas, USA; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore-117600; Faculty of Health Sciences, School of Biomedical Sciences, Curtin University, Bently, Western Australia-6102.
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
keywords: anticancer drug; aromatase inhibitors; breast cancer; molecular docking