title: Rational design and 3D-pharmacophore mapping of 5'-thiourea-substituted alpha-thymidine analogues as mycobacterial TMPK inhibitors.
abstract: Thymidine monophosphate kinase (TMPK) has emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. In this study the receptor-independent (RI) 4D-QSAR formalism has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 5'-thiourea-substituted alpha-thymidine inhibitors. Models were developed for the entire training set and for a subset of the training set consisting of the most potent inhibitors. The optimized (RI) 4D-QSAR models are statistically significant (r(2) = 0.90, q(2) = 0.83 entire set, r(2) = 0.86, q(2) = 0.80 high potency subset) and also possess good predictivity based on test set predictions. The most and least potent inhibitors, in their respective postulated active conformations derived from the models, were docked in the active site of the TMPK crystallographic structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. This model identifies new regions of the inhibitors that contain pharmacophore sites, such as the sugar-pyrimidine ring structure and the region of the 5'-arylthiourea moiety. These new regions of the ligands can be further explored and possibly exploited to identify new, novel, and, perhaps, better antituberculosis inhibitors of TMPKmt. Furthermore, the 3D-pharmacophores defined by these models can be used as a starting point for future receptor-dependent antituberculosis drug design as well as to elucidate candidate sites for substituent addition to optimize ADMET properties of analog inhibitors.
authors.affiliation: Faculty of Pharmaceutical Sciences, Av. Prof. Lineu Prestes, 580, University of Sao Paulo, Sao Paulo, 05508-900, Brazil. carolhorta@usp.br
authors.forename: Carolina H
authors.initials: CH
authors.lastname: Andrade
authors.forename: Kerly F M
authors.initials: KF
authors.lastname: Pasqualoto
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Ferreira
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Hopfinger
mesh_terms: D000465:Algorithms; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors*; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D013890:Thiourea / Q000737:chemistry*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013890:Thiourea; D013936:Thymidine