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Tuberculosis Research and Treatment
Volume 2013 (2013), Article ID 670836, 13 pages
http://dx.doi.org/10.1155/2013/670836
Research Article

Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis

1Laboratory for Simulations and Biomolecular Physics, Advanced Teachers Training College, University of Yaoundé I, P.O. Box 47, Yaoundé, Cameroon
2Centre for Atomic Molecular Physics and Quantum Optics (CEPAMOQ), University of Douala, P.O. Box 8580, Douala, Cameroon
3International Centre for Science and High Technology, UNIDO, Area Science Park, Padriciano 99, 34012 Trieste, Italy
4Laboratoire de Physique Fondamentale et Appliquée, Université d’Abobo-Adjamé, 02 BP 801 Abidjan 02, Cote d’Ivoire
5Cancer Research Institute, Slovak Academy of Sciences, 83391 Bratislava, Slovakia
6Department of Physical Chemistry of Drugs, Faculty of Pharmacy, Comenius University, 83232 Bratislava, Slovakia
7International Centre for Applied Research and Sustainable Technology (ICARST), 81404 Bratislava, Slovakia
8Faculty of Natural Sciences, University of Ss. Cyril and Methodius, 91701 Trnava, Slovakia

Received 30 November 2012; Accepted 12 December 2012

Academic Editor: José R. Lapa e Silva

Copyright © 2013 Luc Calvin Owono Owono et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

We design here new nanomolar antituberculotics, inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt), by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmt cocrystallized with the natural substrate deoxythymidine monophosphate (dTMP) (1GSI) for a training set of 15 thymidine analogues (TMDs) with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. From molecular modeling investigations, the agreement between free energy of complexation ( ) and values explains 94% of the TMPKmt inhibition ( ) by variation of the computed and 92% for the pharmacophore (PH4) model ( ). The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5′-position of the ribose. The best inhibitor reached a predicted of 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents.