title: 3D-Pharmacophore mapping of thymidine-based inhibitors of TMPK as potential antituberculosis agents.
abstract: Tuberculosis (TB) is the primary cause of mortality among infectious diseases. Mycobacterium tuberculosis monophosphate kinase (TMPKmt) is essential to DNA replication. Thus, this enzyme represents a promising target for developing new drugs against TB. In the present study, the receptor-independent, RI, 4D-QSAR method has been used to develop QSAR models and corresponding 3D-pharmacophores for a set of 81 thymidine analogues, and two corresponding subsets, reported as inhibitors of TMPKmt. The resulting optimized models are not only statistically significant with r(2) ranging from 0.83 to 0.92 and q(2) from 0.78 to 0.88, but also are robustly predictive based on test set predictions. The most and the least potent inhibitors in their respective postulated active conformations, derived from each of the models, were docked in the active site of the TMPKmt crystal structure. There is a solid consistency between the 3D-pharmacophore sites defined by the QSAR models and interactions with binding site residues. Moreover, the QSAR models provide insights regarding a probable mechanism of action of the analogues.
authors.affiliation: Department of Pharmacy, Faculty of Pharmaceutical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 580, Bloco 13, Sao Paulo, SP, 05586-900, Brazil. carolhorta@usp.br
authors.forename: Carolina Horta
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 / Q000737:chemistry*; D001665:Binding Sites / Q000187:drug effects; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology*; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors*; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives*; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013936:Thymidine