title: Molecular modelling of human CYP2D6 and molecular docking of a series of ajmalicine- and quinidine-like inhibitors.
abstract: 3D-models were created and refined for CYP2D6 and for its complexes with ajmalicine and quinidine. The influence of the conformation of the enzyme active site on its interaction with ligands was evaluated by performing three series of molecular docking on selected ajmalicine- and quinidine-like inhibitors. The results suggested that the experimental binding values of ajmalicine- and quinidine-like inhibitors better fit with the energetic terms derived from their interaction with structures of CYP2D6 obtained by, respectively, optimizing the ajmalicine/CYP2D6 and the quinidine/CYP2D6 complexes, rather than exploiting the 3D-strucure of the enzyme not subjected to a ligand-induced conformational change. It suggests the relevance of induced-fit phenomena in the biological system of interest.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56100 Pisa, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Saraceno
authors.forename: Alessio
authors.initials: A
authors.lastname: Coi
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Bianucci
mesh_terms: D001665:Binding Sites; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018360:Crystallography, X-Ray; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry* / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D011802:Quinidine / Q000737:chemistry*; D046948:Secologanin Tryptamine Alkaloids / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D003432:Cross-Linking Reagents; D004791:Enzyme Inhibitors; D008024:Ligands; D046948:Secologanin Tryptamine Alkaloids; C005709:raubasine; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine