Analysis of Species-Selectivity of Human, Mouse and Rat Cytochrome P450 1A and 2B Subfamily Enzymes using Molecular Modeling, Docking and Dynamics Simulations
Autor: | S. Parthasarathy, Mohammad Abdulkader Akbarsha, Bagavathy Shanmugam Karthikeyan, Suvaiyarasan Suvaithenamudhan |
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Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Subfamily Molecular model Stereochemistry Molecular Conformation Biophysics Molecular Dynamics Simulation Ligands Biochemistry Mice 03 medical and health sciences 0302 clinical medicine Species Specificity Catalytic Domain Cytochrome P-450 CYP1A1 Animals Humans Homology modeling chemistry.chemical_classification Binding Sites Quinine biology Active site Cytochrome P450 Hydrogen Bonding Cell Biology General Medicine Quinidine Rats Molecular Docking Simulation 030104 developmental biology Enzyme chemistry Docking (molecular) 030220 oncology & carcinogenesis Cytochrome P-450 CYP2B1 biology.protein Software Macromolecule |
Zdroj: | Cell Biochemistry and Biophysics. 76:91-110 |
ISSN: | 1559-0283 1085-9195 |
Popis: | 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. |
Databáze: | OpenAIRE |
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