title: Identification of leads for antiproliferative activity on MDA-MB-435 human breast cancer cells through pharmacophore and CYP1A1-mediated metabolism.
abstract: CYP1A1 is a potential target for anticancer drug development due to its overexpression in certain cancer cells and role in cancer progression. To identify new leads for CYP1A1 mediated anticancer action, we attempted ligand based pharmacophore mapping, virtual screening of databases, molecular docking, MetaSite based filtering, and molecular dynamics simulations. Initial computational and in vitro screening identified 11 compounds from which we identified two lead compounds, ZINC33468944 and ZINC32101539, showed potential antitumor activity on MDA-MB-435 cell lines (GI50 < 0.1 μM) and CYP1A1 inhibition of 0.13 and 0.3 μM, respectively. Furthermore, the lead compounds were evaluated for CYP1A1 mediated metabolism, showing N-hydroxylated metabolites, which have potential of DNA adduct formation and cause cancerous cell death. Analysis of molecular dynamics simulations provided important guidelines for the further modification of the lead compounds. Hence, we claim the lead molecules for further development in anticancer drug discovery.
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
authors.forename: Prajwal P
authors.initials: PP
authors.lastname: Nandekar
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
authors.forename: Kailas
authors.initials: K
authors.lastname: Khomane
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Chaudhary
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Rathod
authors.affiliation: National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, India.
authors.forename: Roshan M
authors.initials: RM
authors.lastname: Borkar
authors.affiliation: National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, India.
authors.forename: Murali Mohan
authors.initials: MM
authors.lastname: Bhandi
authors.affiliation: National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, India.
authors.forename: R
authors.initials: R
authors.lastname: Srinivas
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India. Electronic address: abhays@niper.ac.in.
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
authors.affiliation: Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
authors.forename: Sankar K
authors.initials: SK
authors.lastname: Guchhait
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Bansal
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C000612733:ZINC32101539; C000612732:ZINC33468944; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1
keywords: CYP1A1; EROD assay; Metabolism based virtual screening; Molecular docking; Molecular dynamics; Pharmacophore mapping; Rational design