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Identification of new potential Mycobacterium tuberculosis shikimate kinase inhibitors through molecular docking simulations

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Abstract

Tuberculosis (TB) is the major cause of human mortality from a curable infectious disease, attacking mainly in developing countries. Among targets identified in Mycobacterium tuberculosis genome, enzymes of the shikimate pathway deserve special attention, since they are essential to the survival of the microorganism and absent in mammals. The object of our study is shikimate kinase (SK), the fifth enzyme of this pathway. We applied virtual screening methods in order to identify new potential inhibitors for this enzyme. In this work we employed MOLDOCK program in all molecular docking simulations. Accuracy of enzyme-ligand docking was validated on a set of 12 SK-ligand complexes for which crystallographic structures were available, generating root-mean square deviations below 2.0 Å. Application of this protocol against a commercially available database allowed identification of new molecules with potential to become drugs against TB. Besides, we have identified the binding cavity residues that are essential to intermolecular interactions of this enzyme.

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Acknowledgments

The authors would like to express their gratitude to the reviewers for their valuable comments and suggestions. This work was supported by National Institute of Science and Technology on Tuberculosis (Decit/SCTIE/MS-MCT-CNPq-FNDCTCAPES). W.F.A. Jr. is a research fellow of the National Council for Scientific and Technological Development of Brazil (CNPq). C.P.V. acknowledges a scholarship awarded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).

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Authors and Affiliations

  1. Faculdade de Biociências, Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Laboratório de Bioquímica Estrutural (LaBioQuest), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681, Porto Alegre, RS, 90619-900, Brazil

    Carolina Pasa Vianna & Walter F. de Azevedo Jr.

  2. Programa de Pós Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, RS, Brazil

    Carolina Pasa Vianna & Walter F. de Azevedo Jr.

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  1. Carolina Pasa Vianna
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  2. Walter F. de Azevedo Jr.
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Correspondence to Walter F. de Azevedo Jr..

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Vianna, C.P., de Azevedo, W.F. Identification of new potential Mycobacterium tuberculosis shikimate kinase inhibitors through molecular docking simulations. J Mol Model 18, 755–764 (2012). https://doi.org/10.1007/s00894-011-1113-5

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  • DOI: https://doi.org/10.1007/s00894-011-1113-5

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