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Characterization of dipeptidylcarboxypeptidase of Leishmania donovani: a molecular model for structure based design of antileishmanials

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Abstract

Leishmania donovani dipeptidylcarboxypeptidsae (LdDCP), an angiotensin converting enzyme (ACE) related metallopeptidase has been identified and characterized as a putative drug target for antileishmanial chemotherapy. The kinetic parameters for LdDCP with substrate, Hip-His-Leu were determined as, Km, 4 mM and Vmax, 1.173 μmole/ml/min. Inhibition studies revealed that known ACE inhibitors (captopril and bradykinin potentiating peptide; BPP1) were weak inhibitors for LdDCP as compared to human testicular ACE (htACE) with Ki values of 35.8 nM and 3.9 μM, respectively. Three dimensional model of LdDCP was generated based on crystal structure of Escherichia coli DCP (EcDCP) by means of comparative modeling and assessed using PROSAII, PROCHECK and WHATIF. Captopril docking with htACE, LdDCP and EcDCP and analysis of molecular electrostatic potentials (MEP) suggested that the active site domain of three enzymes has several minor but potentially important structural differences. These differences could be exploited for designing selective inhibitor of LdDCP thereby antileishmanial compounds either by denovo drug design or virtual screening of small molecule databases.

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Acknowledgments

This manuscript carries CDRI communication number 7523. The work is supported by grant from Council of Scientific and Industrial Research (CSIR) funded network project NPW0038 ‘Identification and validation of drug targets for selected pathogen’ and CSIR for financial support to M.S.B and Ashutosh Kumar.

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Authors and Affiliations

  1. Division of Molecular and Structural Biology, Central Drug Research Institute, Lucknow, 226001, India

    Ashutosh Kumar & Mohammad Imran Siddiqi

  2. Division of Biochemistry, Central Drug Research Institute, Lucknow, 226001, India

    Mirza Saqib Baig & Neena Goyal

Authors
  1. Mirza Saqib Baig
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  2. Ashutosh Kumar
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  3. Mohammad Imran Siddiqi
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  4. Neena Goyal
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Corresponding author

Correspondence to Neena Goyal.

Additional information

Mirza Saqib Baig and Ashutosh Kumar have contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Alinment of active site (6.5 Ao) residues of htACE, LdDCP and EcDCP. (TIFF 422 kb)

10822_2009_9315_MOESM2_ESM.tif

Ramachandran plot (LdDCP) of ¢/ψ distribution produced by PROCHECK validation package. The most favored and favored regions are colored red and dark yellow, respectively. Light yellow region are generally allowed, disallowed regions are white. (TIFF 4,203 kb)

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Baig, M.S., Kumar, A., Siddiqi, M.I. et al. Characterization of dipeptidylcarboxypeptidase of Leishmania donovani: a molecular model for structure based design of antileishmanials. J Comput Aided Mol Des 24, 77–87 (2010). https://doi.org/10.1007/s10822-009-9315-y

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  • DOI: https://doi.org/10.1007/s10822-009-9315-y

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