Characterization of dipeptidylcarboxypeptidase of <Emphasis Type="Italic">Leishmania donovani</Emphasis>: a molecular model for structure based design of antileishmanials |
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Authors: | Mirza Saqib Baig Ashutosh Kumar Mohammad Imran Siddiqi Neena Goyal |
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Institution: | (1) Division of Molecular and Structural Biology, Central Drug Research Institute, Lucknow, 226001, India;(2) Division of Biochemistry, Central Drug Research Institute, Lucknow, 226001, India; |
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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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