title: Characterization of differences in substrate specificity among CYP1A1, CYP1A2 and CYP1B1: an integrated approach employing molecular docking and molecular dynamics simulations.
abstract: Recent trends in new drug discovery of anticancer drugs have made oncologists more aware of the fact that the new drug discovery must target the developing mechanism of tumorigenesis to improve the therapeutic efficacy of antineoplastic drugs. The drugs designed are expected to have high affinity towards the novel targets selectively. Current research highlights overexpression of CYP450s, particularly cytochrome P450 1A1 (CYP1A1), in tumour cells, representing a novel target for anticancer therapy. However, the CYP1 family is identified as posing significant problems in selectivity of anticancer molecules towards CYP1A1. Three members have been identified in the human CYP1 family: CYP1A1, CYP1A2 and CYP1B1. Although sequences of the three isoform have high sequence identity, they have distinct substrate specificities. The understanding of macromolecular features that govern substrate specificity is required to understand the interplay between the protein function and dynamics, design novel antitumour compounds that could be specifically metabolized by only CYP1A1 to mediate their antitumour activity and elucidate the reasons for differences in substrate specificity profile among the three proteins. In the present study, we employed a combination of computational methodologies: molecular docking and molecular dynamics simulations. We utilized eight substrates for elucidating the difference in substrate specificity of the three isoforms. Lastly, we conclude that the substrate specificity of a particular substrate depends upon the type of the active site residues, the dynamic motions in the protein structure upon ligand binding and the physico-chemical characteristics of a particular ligand. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar-, 160062 Punjab, India.
authors.forename: Siddharth S
authors.initials: SS
authors.lastname: Kesharwani
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar-, 160062 Punjab, India.
authors.forename: Prajwal P
authors.initials: PP
authors.lastname: Nandekar
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar-, 160062 Punjab, India.
authors.forename: Preeti
authors.initials: P
authors.lastname: Pragyan
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar-, 160062 Punjab, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Rathod
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector 67, S.A.S. Nagar-, 160062 Punjab, India.
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000737:chemistry* / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000737:chemistry* / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1 / Q000737:chemistry* / Q000378:metabolism; D062126:Databases, Chemical; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D013379:Substrate Specificity
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; C569463:CYP1A1 protein, human; C504573:CYP1A2 protein, human; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1
keywords: CYP1 family; molecular docking; molecular dynamics simulation; substrate specificity