title: Characterization of dipeptidylcarboxypeptidase of Leishmania donovani: a molecular model for structure based design of antileishmanials.
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 micromole/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 microM, 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.
authors.affiliation: Division of Biochemistry, Central Drug Research Institute, Lucknow 226001, India.
authors.forename: Mirza Saqib
authors.initials: MS
authors.lastname: Baig
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Kumar
authors.forename: Mohammad Imran
authors.initials: MI
authors.lastname: Siddiqi
authors.forename: Neena
authors.initials: N
authors.lastname: Goyal
mesh_terms: D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D002216:Captopril / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D007893:Leishmania donovani / Q000201:enzymology*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D007703:Peptidyl-Dipeptidase A / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D016415:Sequence Alignment; D055672:Static Electricity; D040681:Structural Homology, Protein
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000981:Antiprotozoal Agents; D002216:Captopril; D007703:Peptidyl-Dipeptidase A