Molecular dynamics simulations of peptide inhibitors complexed with Trypanosoma cruzi trypanothione reductase.
The drugs against tropical neglected diseases, especially Chagas' Disease, were launched more than 30 years ago, and the development of resistance requires the discovery of new and more effective chemotherapeutic agents. Trypanosoma cruzi has a redox enzyme called trypanothione reductase which was successfully inhibited for peptide derivatives (McKie et al., Amino Acids, 2001, 20: 145). This work aims at studying the mechanism of inhibition of this enzyme through molecular dynamics simulations and evaluating the behavior of some derivatives when inhibiting this protein. We should affirm that any particular molecular dynamics analysis tools (Hbond pattern, 3-D root-mean-square deviation, solvent accessible surface area, etc.) cannot be used apart from the others to justify completely these peptides inhibitory patterns. Based on our results, we reproduced the experimental data and, moreover, we discriminated against a new site in enzyme aperture, which can assist the development of powerful inhibitors against trypanothione reductase enzyme.
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Avenida Carlos Chagas Filho 373, Bloco D, Sala D-030, Cidade Universitária, Ilha do Fundão, 21941-902 Rio de Janeiro, RJ, Brasil. samuelpita@biof.ufrj.br
Samuel
S
Silva Da Rocha Pita
Paulo Ricardo
PR
Batista
Magaly Girão
MG
Albuquerque
Pedro Geraldo
PG
Pascutti
D020134:Catalytic Domain; D014355:Chagas Disease / Q000188:drug therapy / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000737:chemistry / Q000201:enzymology*
D004791:Enzyme Inhibitors; D010455:Peptides; D014344:Trypanocidal Agents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase