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

Abstract

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.

Chemotherapy of leishmaniasis: present challenges

“…The opposite strategy elects a target that has been deemed of importance for the parasite and ideally is absent in the host. Examples of targets that have been used for drug screening purposes are thypanothione reductase (Richardson et al 2009; Pandey et al 2015), N-myristoyltransferase (Bell et al 2012; Rackham et al 2015), inositol phosphorylceramide synthase (Mina et al 2010), dipeptidylcarboxypeptidase (Gangwar et al 2012), among others. Target-based drug screening has the disadvantage of not always translating into parasite killing or in vivo activity, as has been extensively demonstrated by target-based efforts.…”

Proteinase Inhibitors: A Promising Drug Class for Treating Leishmaniasis

“…MP-inhibiting synthetic compounds have been selected through in silico analysis from databanks, and these compounds were able to block L. (L.) donovani proliferation in vitro. Specifically, these compounds inhibit parasite dipeptidyl carboxypeptidase, which has been established as a putative target for antileishmanial chemotherapy [121].…”