title: Improved Homology Model of the Human all-trans Retinoic Acid Metabolizing Enzyme CYP26A1.
abstract: A new CYP26A1 homology model was built based on the crystal structure of cyanobacterial CYP120A1. The model quality was examined for stereochemical accuracy, folding reliability, and absolute quality using a variety of different bioinformatics tools. Furthermore, the docking capabilities of the model were assessed by docking of the natural substrate all-trans-retinoic acid (atRA), and a group of known azole- and tetralone-based CYP26A1 inhibitors. The preferred binding pose of atRA suggests the (4S)-OH-atRA metabolite production, in agreement with recently available experimental data. The distances between the ligands and the heme group iron of the enzyme are in agreement with corresponding distances obtained for substrates and azole inhibitors for other cytochrome systems. The calculated theoretical binding energies agree with recently reported experimental data and show that the model is capable of discriminating between natural substrate, strong inhibitors (R116010 and R115866), and weak inhibitors (liarozole, fluconazole, tetralone derivatives).
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Hail, P. O. Box 2440, 81451 Hail, Saudi Arabia. m.awadalla@uoh.edu.sa.
authors.forename: Mohamed K A
authors.initials: MK
authors.lastname: Awadalla
authors.affiliation: Department of Clinical Pharmacology, College of Pharmacy, University of Hail, P. O. Box 2440, 81451 Hail, Saudi Arabia. th.alshammari@uoh.edu.sa.
authors.forename: Thamir M
authors.initials: TM
authors.lastname: Alshammari
authors.affiliation: Department of Chemistry and Molecular Biology, University of Gothenburg, 40530 Gothenburg, Sweden. leif.eriksson@chem.gu.se.
authors.forename: Leif A
authors.initials: LA
authors.lastname: Eriksson
authors.affiliation: Computational Chemistry and Biology Group, Facultad de Química, UdelaR, 11800 Montevideo, Uruguay. psaenz@fq.edu.uy.
authors.forename: Patricia
authors.initials: P
authors.lastname: Saenz-Méndez
mesh_terms: D020134:Catalytic Domain; D006418:Heme / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D045792:Norisoprenoids / Q000737:chemistry; D011485:Protein Binding; D000072516:Retinoic Acid 4-Hydroxylase / Q000737:chemistry*; D044024:Tetralones / Q000737:chemistry; D014212:Tretinoin / Q000737:chemistry*
chemical_list: D045792:Norisoprenoids; D044024:Tetralones; D006418:Heme; D014212:Tretinoin; D000072516:Retinoic Acid 4-Hydroxylase
keywords: CYP26A1; RAMBA; homology model; molecular docking; retinoic acid