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Tuberc Res Treat. 2013;2013:670836. doi: 10.1155/2013/670836. Epub 2013 Mar 24.

Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis.

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  • 1Laboratory for Simulations and Biomolecular Physics, Advanced Teachers Training College, University of Yaoundé I, P.O. Box 47, Yaoundé, Cameroon ; Centre for Atomic Molecular Physics and Quantum Optics (CEPAMOQ), University of Douala, P.O. Box 8580, Douala, Cameroon ; International Centre for Science and High Technology, UNIDO, Area Science Park, Padriciano 99, 34012 Trieste, Italy.

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 (ΔΔG com) and K i values explains 94% of the TMPKmt inhibition (pK i = -0.2924ΔΔG com + 3.234; R (2) = 0.94) by variation of the computed ΔΔG com and 92% for the pharmacophore (PH4) model (pK i = 1.0206 × pK i (pred) - 0.0832, R (2) = 0.92). 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 K i 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.

PMID:
23634301
[PubMed]
PMCID:
PMC3619541
Free PMC Article

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