title: Effects of protein flexibility and active site water molecules on the prediction of sites of metabolism for cytochrome P450 2C19 substrates.
abstract: Structure-based prediction of sites of metabolism (SOMs) mediated by cytochrome P450s (CYPs) is of great interest in drug discovery and development. However, protein flexibility and active site water molecules remain a challenge for accurate SOM prediction. CYP2C19 is one of the major drug-metabolizing enzymes and has attracted considerable attention because of its polymorphism and capability of metabolizing ∼7% clinically used drugs. In this study, we systematically evaluated the effects of protein flexibility and active site water molecules on SOM prediction for CYP2C19 substrates. Multiple conformational sampling techniques including GOLD flexible residues sampling, molecular dynamics (MD) and tCONCOORD side-chain sampling were adopted for assessing the influence of protein flexibility on SOM prediction. The prediction accuracy could be significantly improved when protein flexibility was considered using the tCONCOORD sampling method, which indicated that the side-chain conformation was important for accurate prediction. However, the inclusion of the crystallographic or MD-derived water molecule(s) does not necessarily improve the prediction accuracy. Finally, a combination of docking results with SMARTCyp was found to be able to increase the SOM prediction accuracy.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. whli@ecust.edu.cn ytang234@ecust.edu.cn.
authors.forename: Junhao
authors.initials: J
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. whli@ecust.edu.cn ytang234@ecust.edu.cn.
authors.forename: Jinya
authors.initials: J
authors.lastname: Cai
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. whli@ecust.edu.cn ytang234@ecust.edu.cn.
authors.forename: Haixia
authors.initials: H
authors.lastname: Su
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. whli@ecust.edu.cn ytang234@ecust.edu.cn.
authors.forename: Hanwen
authors.initials: H
authors.lastname: Du
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. whli@ecust.edu.cn ytang234@ecust.edu.cn.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. whli@ecust.edu.cn ytang234@ecust.edu.cn.
authors.forename: Shihui
authors.initials: S
authors.lastname: Ding
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. whli@ecust.edu.cn ytang234@ecust.edu.cn.
authors.forename: Guixia
authors.initials: G
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. whli@ecust.edu.cn ytang234@ecust.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China. whli@ecust.edu.cn ytang234@ecust.edu.cn.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D065731:Cytochrome P-450 CYP2C19 / Q000737:chemistry* / Q000378:metabolism*; D030562:Databases, Protein; D062105:Molecular Docking Simulation; D015203:Reproducibility of Results; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry*
chemical_list: D014867:Water; D065731:Cytochrome P-450 CYP2C19