title: Evaluation of influence of single nucleotide polymorphisms in cytochrome P450 2B6 on substrate recognition using computational docking and molecular dynamics simulation.
abstract: In this study, we investigated the influence of single nucleotide polymorphisms on the conformation of mutated cytochrome P450 (CYP) 2B6 proteins using molecular dynamics (MD) simulation. Some of these mutations influence drug metabolism activities, leading to individual variations in drug efficacy and pharmacokinetics. Using computational docking, we predicted the structure of the complex between the antimalarial agent artemether and CYP2B6 whose conformations were obtained by MD simulation. The simulation demonstrated that the entire structure of the protein changes even when a single residue is mutated. Moreover, the structural flexibility is affected by the mutations and it may influence the enzyme activity. The results suggest that some of the inactive mutants cannot recognize artemether due to structural changes caused by the mutation.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Aoba-ku, Sendai, Miyagi, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, Aoba-ku, Sendai, Miyagi, Japan.
authors.forename: Ohgi
authors.initials: O
authors.lastname: Takahashi
authors.affiliation: Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai, Miyagi, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiratsuka
authors.affiliation: School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yamaotsu
authors.affiliation: School of Pharmacy, Kitasato University, Minato-ku, Tokyo, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Yurie
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan; Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Oda
mesh_terms: D000077549:Artemether; D037621:Artemisinins / Q000737:chemistry; D065702:Cytochrome P-450 CYP2B6 / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D013696:Temperature
chemical_list: D037621:Artemisinins; D008024:Ligands; D000077549:Artemether; D065702:Cytochrome P-450 CYP2B6