title: Analysis of Species-Selectivity of Human, Mouse and Rat Cytochrome P450 1A and 2B Subfamily Enzymes using Molecular Modeling, Docking and Dynamics Simulations.
abstract: Cytochrome P450 (CYP) 1A and 2B subfamily enzymes are important drug metabolizing enzymes, and are highly conserved across species in terms of sequence homology. However, there are major to minor structural and macromolecular differences which provide for species-selectivity and substrate-selectivity. Therefore, species-selectivity of CYP1A and CYP2B subfamily proteins across human, mouse and rat was analyzed using molecular modeling, docking and dynamics simulations when the chiral molecules quinine and quinidine were used as ligands. The three-dimensional structures of 17 proteins belonging to CYP1A and CYP2B subfamilies of mouse and rat were predicted by adopting homology modeling using the available structures of human CYP1A and CYP2B proteins as templates. Molecular docking and dynamics simulations of quinine and quinidine with CYP1A subfamily proteins revealed the existence of species-selectivity across the three species. On the other hand, in the case of CYP2B subfamily proteins, no role for chirality of quinine and quinidine in forming complexes with CYP2B subfamily proteins of the three species was indicated. Our findings reveal the roles of active site amino acid residues of CYP1A and CYP2B subfamily proteins and provide insights into species-selectivity of these enzymes across human, mouse, and rat.
authors.affiliation: Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli, 620 024, Tamil Nadu, India.|Mahatma Gandhi-Doerenkamp Center (MGDC) for Alternatives to Use of Animals in Life Science Education, Bharathidasan University, Tiruchirappalli, 620 024, Tamil Nadu, India.
authors.forename: Bagavathy Shanmugam
authors.initials: BS
authors.lastname: Karthikeyan
authors.affiliation: Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli, 620 024, Tamil Nadu, India.
authors.forename: Suvaiyarasan
authors.initials: S
authors.lastname: Suvaithenamudhan
authors.affiliation: Mahatma Gandhi-Doerenkamp Center (MGDC) for Alternatives to Use of Animals in Life Science Education, Bharathidasan University, Tiruchirappalli, 620 024, Tamil Nadu, India.
authors.forename: Mohammad Abdulkader
authors.initials: MA
authors.lastname: Akbarsha
authors.affiliation: Department of Bioinformatics, School of Life Sciences, Bharathidasan University, Tiruchirappalli, 620 024, Tamil Nadu, India. bdupartha@gmail.com.
authors.forename: Subbiah
authors.initials: S
authors.lastname: Parthasarathy
mesh_terms: D000818:Animals; D001665:Binding Sites; D020134:Catalytic Domain; D019363:Cytochrome P-450 CYP1A1 / Q000737:chemistry / Q000378:metabolism*; D019362:Cytochrome P-450 CYP2B1 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011802:Quinidine / Q000737:chemistry / Q000378:metabolism; D011803:Quinine / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D012984:Software; D013045:Species Specificity
chemical_list: D008024:Ligands; D011803:Quinine; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D011802:Quinidine
keywords: Cytochrome P450; Glide docking; Homology modeling; Molecular dynamics simulations; Schrödinger software suite; Species selectivity