title: Effects of protein flexibility on the site of metabolism prediction for CYP2A6 substrates.
abstract: Structure-based prediction for the site of metabolism (SOM) of a compound metabolized by human cytochrome P450s (CYPs) is highly beneficial in drug discovery and development. However, the flexibility of the CYPs' active site remains a huge challenge for accurate SOM prediction. Compared with other CYPs, the active site of CYP2A6 is relatively small and rigid. To address the impact of the flexibility of CYP2A6 active site residues on the SOM prediction for substrates, in this work, molecular dynamics (MD) simulations and molecular docking were used to predict the SOM of 96 CYP2A6 substrates. Substrates with known SOM were docked into the snapshot structures from MD simulations and the crystal structures of CYP2A6. Compared to the crystal structures, the protein structures obtained from MD simulations showed more accurate prediction for SOM. Our results indicated that the flexibility of the active site of CYP2A6 significantly affects the SOM prediction results. Further analysis for the 40 substrates with definite Km values showed that the prediction accuracy for the low Km substrates is comparable to that by ligand-based methods.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors.forename: Yayun
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
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, 130 Meilong Road, Shanghai 200237, China. Electronic address: whli@ecust.edu.cn.
authors.forename: Weihua
authors.initials: W
authors.lastname: Li
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. Electronic address: ytang234@ecust.edu.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
mesh_terms: D065637:Cytochrome P-450 CYP2A6 / Q000737:chemistry*; D062105:Molecular Docking Simulation / Q000379:methods*; D056004:Molecular Dynamics Simulation
chemical_list: C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6
keywords: CYP2A6; Flexibility; Molecular docking; Molecular dynamics simulations; Site of metabolism