Journal of Computer-Aided Molecular Design

, Volume 32, Issue 12, pp 1315–1336 | Cite as

Mycobacterium tuberculosis serine/threonine protein kinases: structural information for the design of their specific ATP-competitive inhibitors

  • Julio CaballeroEmail author
  • Alejandro Morales-Bayuelo
  • Carlos Navarro-Retamal


In the last decades, human protein kinases (PKs) have been relevant as targets in the development of novel therapies against many diseases, but the study of Mycobacterium tuberculosis PKs (MTPKs) involved in tuberculosis pathogenesis began much later and has not yet reached an advanced stage of development. To increase knowledge of these enzymes, in this work we studied the structural features of MTPKs, with focus on their ATP-binding sites and their interactions with inhibitors. PknA, PknB, and PknG are the most studied MTPKs, which were previously crystallized; ATP-competitive inhibitors have been designed against them in the last decade. In the current work, reported PknA, PknB, and PknG inhibitors were extracted from literature and their orientations inside the ATP-binding site were proposed by using docking method. With this information, interaction fingerprints were elaborated, which reveal the more relevant residues for establishing chemical interactions with inhibitors. The non-crystallized MTPKs PknD, PknF, PknH, PknJ, PknK, and PknL were also studied; their three-dimensional structural models were developed by using homology modeling. The main characteristics of MTPK ATP-binding sites (the non-crystallized and crystallized MTPKs, including PknE and PknI) were accounted; schemes of the main polar and nonpolar groups inside their ATP-binding sites were constructed, which are suitable for a major understanding of these proteins as antituberculotic targets. These schemes could be used for establishing comparisons between MTPKs and human PKs in order to increase selectivity of MTPK inhibitors. As a key tool for guiding medicinal chemists interested in the design of novel MTPK inhibitors, our work provides a map of the structural elements relevant for the design of more selective ATP-competitive MTPK inhibitors.


Mycobacterium tuberculosis protein kinases Protein kinases selectivity Molecular docking Interaction fingerprings 



Thanks to the funds of FONDECYT postdoctoral project N0 3150035 (AMB and JC). JC also acknowledges funds of FONDECYT Regular N0 1170718. CNR also acknowledges funds of FONDECYT postdoctoral project N0 3170434.

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Authors and Affiliations

  1. 1.Centro de Bioinformática y Simulación Molecular (CBSM)Universidad de TalcaTalcaChile

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