2. Academic Validation
  3. Identification of leads for antiproliferative activity on MDA-MB-435 human breast cancer cells through pharmacophore and CYP1A1-mediated metabolism

Identification of leads for antiproliferative activity on MDA-MB-435 human breast cancer cells through pharmacophore and CYP1A1-mediated metabolism

  • Eur J Med Chem. 2016 Jun 10:115:82-93. doi: 10.1016/j.ejmech.2016.02.061.
Prajwal P Nandekar 1,  Kailas Khomane 2,  Vikas Chaudhary 3,  Vijay P Rathod 1,  Roshan M Borkar 4,  Murali Mohan Bhandi 4,  R Srinivas 4,  Abhay T Sangamwar 5,  Sankar K Guchhait 3,  Arvind K Bansal 2
Affiliations

Affiliations

  • 1 Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
  • 2 Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
  • 3 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India.
  • 4 National Centre for Mass Spectrometry, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad, India.
  • 5 Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Punjab, India. Electronic address: abhays@niper.ac.in.
PMID: 26994845 DOI: 10.1016/j.ejmech.2016.02.061
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.

Keywords

CYP1A1; EROD assay; Metabolism based virtual screening; Molecular docking; Molecular dynamics; Pharmacophore mapping; Rational design.

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