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Homology modeling and atomic level binding study of Leishmania MAPK with inhibitors

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Abstract

The current therapy for leishmaniasis is not sufficient and it has two severe drawbacks, host-toxicity and drug resistance. The substantial knowledge of parasite biology is not yet translating into novel drugs for leishmaniasis. Based on this observation, a 3D structural model of Leishmania mitogen-activated protein kinase (MAPK) homologue has been developed, for the first time, by homology modeling and molecular dynamics simulation techniques. The model provided clear insight in its structure features, i.e. ATP binding pocket, phosphorylation lip, and common docking site. Sequence-structure homology recognition identified Leishmania CRK3 (LCRK3) as a distant member of the MAPK superfamily. Multiple sequence alignment and 3D structure model provided the putative ATP binding pocket of Leishmania with respect to human ERK2 and LCRK3. This analysis was helpful in identifying the binding sites and molecular function of the Leishmania specific MAPK homologue. Molecular docking study was performed on this 3D structural model, using different classes of competitive ATP inhibitors of LCRK3, to check whether they exhibit affinity and could be identified as Leishmania MAPK specific inhibitors. It is well known that MAP kinases are extracellular signal regulated kinases ERK1 and ERK2, which are components of the Ras-MAPK signal transduction pathway which is complexed with HDAC4 protein, and their inhibition is of significant therapeutic interest in cancer biology. In order to understand the mechanism of action, docking of indirubin class of molecules to the active site of histone deacetylase 4 (HDAC4) protein is performed, and the binding affinity of the protein-ligand interaction was computed. The new structural insights obtained from this study are all consistent with the available experimental data, suggesting that the homology model of the Leishmania MAPK and its ligand interaction modes are reasonable. Further the comparative molecular electrostatic potential and cavity depth analysis of Leishmania MAPK and human ERK2 suggested several important differences in its ATP binding pocket. Such differences could be exploited in the future for designing Leishmania specific MAPK inhibitors.

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Acknowledgments

This research was supported by grants from the Ministry of Chemicals and Fertilizers, Govt. of India, India. CGM also acknowledges the Department of Biotechnology (IFD-Dy. No.102/ IFD/SAN/ 884/2006-2009) New Delhi, India for partial financial support of this work. PS is recipient of Senior Research Fellowship from Department of Biotechnology, India.

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Authors and Affiliations

  1. Centre for Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, 160 062, Punjab, India

    Mahendra Awale, Vivek Kumar, Parameswaran Saravanan & C. Gopi Mohan

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  1. Mahendra Awale
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  2. Vivek Kumar
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  3. Parameswaran Saravanan
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  4. C. Gopi Mohan
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Corresponding author

Correspondence to C. Gopi Mohan.

Supplementary material

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Supplementary material Figure 1s

Errat plot of Leishmania MAPK model (DOC 74 kb)

Supplementary materia Figure 2s

Scatter plot of actual in vitro activities (ED50) versus the binding energy computed using AutoDock software (DOC 35 kb)

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Awale, M., Kumar, V., Saravanan, P. et al. Homology modeling and atomic level binding study of Leishmania MAPK with inhibitors. J Mol Model 16, 475–488 (2010). https://doi.org/10.1007/s00894-009-0565-3

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  • DOI: https://doi.org/10.1007/s00894-009-0565-3

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