title: Docking and molecular dynamics simulation of quinone compounds with trypanocidal activity.
abstract: In this work, two different docking programs were used, AutoDock and FlexX, which use different types of scoring functions and searching methods. The docking poses of all quinone compounds studied stayed in the same region in the trypanothione reductase. This region is a hydrophobic pocket near to Phe396, Pro398 and Leu399 amino acid residues. The compounds studied displays a higher affinity in trypanothione reductase (TR) than glutathione reductase (GR), since only two out of 28 quinone compounds presented more favorable docking energy in the site of human enzyme. The interaction of quinone compounds with the TR enzyme is in agreement with other studies, which showed different binding sites from the ones formed by cysteines 52 and 58. To verify the results obtained by docking, we carried out a molecular dynamics simulation with the compounds that presented the highest and lowest docking energies. The results showed that the root mean square deviation (RMSD) between the initial and final pose were very small. In addition, the hydrogen bond pattern was conserved along the simulation. In the parasite enzyme, the amino acid residues Leu399, Met400 and Lys402 are replaced in the human enzyme by Met406, Tyr407 and Ala409, respectively. In view of the fact that Leu399 is an amino acid of the Z site, this difference could be explored to design selective inhibitors of TR.
authors.affiliation: Departamento de Química e Física Molecular, Instituto de Química de São Carlos, Universidade de São Paulo, SP, Brasil.
authors.forename: Fábio Alberto
authors.initials: FA
authors.lastname: de Molfetta
authors.forename: Renato Ferreira
authors.initials: RF
authors.lastname: de Freitas
authors.forename: Albérico Borges Ferreira
authors.initials: AB
authors.lastname: da Silva
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Montanari
mesh_terms: D000596:Amino Acids; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D015195:Drug Design; D005980:Glutathione Reductase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011809:Quinones / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014344:Trypanocidal Agents / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D011809:Quinones; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005980:Glutathione Reductase