Journal of Molecular Modeling

, Volume 19, Issue 1, pp 179–192 | Cite as

Structural and chemical basis for enhanced affinity to a series of mycobacterial thymidine monophosphate kinase inhibitors: fragment-based QSAR and QM/MM docking studies

  • Renata V. Bueno
  • Ney R. Toledo
  • Bruno J. Neves
  • Rodolpho C. Braga
  • Carolina H. Andrade
Original Paper

Abstract

Tuberculosis (TB) still remains one of the most deadly infectious diseases. Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) has emerged as an attractive molecular target for the design of a novel class of anti-TB agents since blocking it will affect the pathways involved in DNA replication. Aiming at shedding some light on structural and chemical features that are important for the affinity of thymidine derivatives to TMPKmt, we have employed a special fragment-based method to develop robust quantitative structure-activity relationship models for a large and chemically diverse series of thymidine-based analogues. Significant statistical parameters (r2 = 0.94, q2 = 0.76, r2pred = 0.89) were obtained, indicating the reliability of the hologram QSAR model in predicting the biological activity of untested compounds. The 2D model was then used to predict the potency of an external test set, and the predicted values obtained from the HQSAR model were in good agreement with the experimental results. We have accordingly designed novel TMPKmt inhibitors by utilizing the fragments proposed by HQSAR analysis and predicted with good activity in the developed models. The new designed compounds also presented drug-like characteristics based on Lipinski’s rule of 5. The generated molecular recognition patterns gathered from the HQSAR analysis combined with quantum mechanics/molecular mechanics (QM/MM) docking studies, provided important insights into the chemical and structural basis involved in the molecular recognition process of this series of thymidine analogues and should be useful for the design of new potent anti-TB agents.

Keywords

Fragment-based HQSAR QM/MM docking Thymidine monophosphate kinase Tuberculosis 

Notes

Acknowledgments

The authors would like to thank Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Fundação de Amparo à Pesquisa do Estado de Goiás (FAPEG) for financial support.

Supplementary material

894_2012_1527_MOESM1_ESM.doc (402 kb)
ESM 1(DOC 401 kb)

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Renata V. Bueno
    • 1
  • Ney R. Toledo
    • 1
  • Bruno J. Neves
    • 1
  • Rodolpho C. Braga
    • 1
  • Carolina H. Andrade
    • 1
  1. 1.Laboratório de Planejamento de Fármacos e Estudos de Metabolismo por Modelagem Molecular (LabMol), Faculdade de FarmáciaUniversidade Federal de GoiásGoianiaBrazil

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