title: Molecular modeling of Mycobacterium tuberculosis dUTpase: docking and catalytic mechanism studies.
abstract: Mycobacterium tuberculosis is a leading cause of infectious disease in the world today. This outlook is aggravated by a growing number of M. tuberculosis infections in individuals who are immunocompromised as a result of HIV infections. Thus, new and more potent anti-TB agents are necessary. Therefore, dUTpase was selected as a target enzyme to combat M. tuberculosis. In this work, molecular modeling methods involving docking and QM/MM calculations were carried out to investigate the binding orientation and predict binding affinities of some potential dUTpase inhibitors. Our results suggest that the best potential inhibitor investigated, among the compounds studied in this work, is the compound dUPNPP. Regarding the reaction mechanism, we concluded that the decisive stage for the reaction is the stage 1. Furthermore, it was also observed that the compounds with a -1 electrostatic charge presented lower activation energy in relation to the compounds with a -2 charge.
authors.affiliation: Department of Chemistry, Federal University of Lavras, CEP 37200-000 Lavras, Minas Gerais, Brazil. teo@dqi.ufla.br
authors.forename: Teodorico C
authors.initials: TC
authors.lastname: Ramalho
authors.forename: Melissa S
authors.initials: MS
authors.lastname: Caetano
authors.forename: Daniela
authors.initials: D
authors.lastname: Josa
authors.forename: Gustavo P
authors.initials: GP
authors.lastname: Luz
authors.forename: Elisangela A
authors.initials: EA
authors.lastname: Freitas
authors.forename: Elaine F F
authors.initials: EF
authors.lastname: da Cunha
mesh_terms: D000995:Antitubercular Agents / Q000378:metabolism* / Q000494:pharmacology; D055162:Biocatalysis; D015195:Drug Design; D004734:Energy Metabolism; D004735:Energy Transfer; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase