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

Baig, Mirza S.; Kumar, Ashutosh; Siddiqi, Mohammad Imran; Goyal, Neena

doi:10.1007/s10822-009-9315-y

Cited by 11 publications

(6 citation statements)

References 38 publications

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“…Figure 3E depicts the docking of d ‐captopril in active site of homology model of LdDCP. As observed earlier (17), d ‐captopril may chelate to zinc atom via carboxylate oxygen. In this preferred mode of binding, carbonyl group of captopril can interact with hydroxyl group of Tyr604.…”

Section: Resultssupporting

confidence: 71%

“…Captopril, an ACE‐specific inhibitor was able to inhibit significantly LdDCP enzyme activity and the parasite growth which strongly suggests that this newly identified DCP could serve as drug target in Leishmania . The 3D structural model for LdDCP has already been constructed using the X‐ray crystal structure of DCP from E. coli as template (17). Captopril docking with hACE, LdDCP, and EcDCP and analysis of molecular electrostatic potentials suggested that the active site domain of these three enzymes has several minor but potentially important structural differences.…”

Section: Resultsmentioning

confidence: 99%

“…As expected, all compounds exhibited competitive mode of inhibition. Compound IV appeared to be the most potent inhibitor of LdDCP with K i value of 20 n m which was less than the K i value of captopril (35.8 n m ) (17). That was followed by compound I (4halo = Br) and III (4halo = F).…”

Section: Resultsmentioning

confidence: 99%

“…The binding profile of d ‐captopril docked to LdDCP (17) was used for the generation of the pharmacophore model. Three‐dimensional structures of all the ligand molecules involved in docking studies were modeled with the sybyl 7.1 molecular modeling program (Tripos Associates, St Louis, MO, USA) using the sketch approach.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, three-dimensional model of LdDCP was generated based on crystal structure of E. coli DCP (EcDCP) by means of comparative modeling (17). In the present study, we applied a virtual screening approach to identify potential candidate ligands for LdDCP.…”

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confidence: 99%

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Identification of Novel Inhibitors of Dipeptidylcarboxypeptidase of Leishmania donovani via Ligand‐Based Virtual Screening and Biological Evaluation

Gangwar¹,

Baig²,

Shah³

et al. 2011

Chem Biol Drug Des

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Current treatment of leishmaniasis is based on chemotherapy, which relies on a handful of drugs with serious limitations, such as high cost, toxicity, and lack of efficacy in endemic regions. Therefore, development of new, effective, and affordable anti-leishmanial drugs is a global health priority. Dipeptidylcarboxypeptidase has been characterized and established as a drug target for antileishmanial drug discovery. We virtually screened a large chemical library of 15 452 compounds against a 3D model of dipeptidylcarboxypeptidase to identify novel inhibitors. The initial virtual screening using a ligand-based pharmacophore model identified 103 compounds. Forty-six compounds were shortlisted based on the docking scores and other scoring functions. Further, these compounds were subjected to biological assay, and four of them belonging to two chemical classes were identified as the lead compounds. Identification of these novel and chemically diverse inhibitors should provide leads to be optimized into candidates to treat these protozoan infections.

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of Novel Inhibitors of Dipeptidylcarboxypeptidase of Leishmania donovani via Ligand‐Based Virtual Screening and Biological Evaluation

Gangwar¹,

Baig²,

Shah³

et al. 2011

Chem Biol Drug Des

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A proteogenomic approach to map the proteome of an unsequenced pathogen – Leishmania donovani

et al. 2012

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Visceral leishmaniasis or kala azar is the most severe form of leishmaniasis and is caused by the protozoan parasite Leishmania donovani. There is no published report on L. donovani genome sequence available till date, although the genome sequences of three related Leishmania species are already available. Thus, we took a proteogenomic approach to identify proteins from two different life stages of L. donovani. From our analysis of the promastigote (insect) and amastigote (human) stages of L. donovani, we identified a total of 22,322 unique peptides from a homology-based search against proteins from three Leishmania species. These peptides were assigned to 3711 proteins in L. infantum, 3287 proteins in L. major, and 2433 proteins in L. braziliensis. Of the 3711 L. donovani proteins that were identified, the expression of 1387 proteins was detectable in both life stages of the parasite, while 901 and 1423 proteins were identified only in promastigotes and amastigotes life stages, respectively. In addition, we also identified 13 N-terminally and one C-terminally extended proteins based on the proteomic data search against the six-frame translated genome of the three related Leishmania species. Here, we report results from proteomic profiling of L. donovani, an organism with an unsequenced genome.

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Drug Targets, Drug Effectors, and Drug Targeting and Delivery

Loiseau

Barratt

2012

Drug Resistance in Leishmania Parasites

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

Cited by 11 publications

References 38 publications

Identification of Novel Inhibitors of Dipeptidylcarboxypeptidase of Leishmania donovani via Ligand‐Based Virtual Screening and Biological Evaluation

Identification of Novel Inhibitors of Dipeptidylcarboxypeptidase of Leishmania donovani via Ligand‐Based Virtual Screening and Biological Evaluation

A proteogenomic approach to map the proteome of an unsequenced pathogen – Leishmania donovani

Drug Targets, Drug Effectors, and Drug Targeting and Delivery

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