title: Discovery of novel anti-leishmanial agents targeting LdLip3 lipase.
abstract: Leishmaniasis is a neglected tropical disease, caused by several species of Leishmania. Being an opportunistic lipid-scavenging pathogen, Leishmania relies extensively on lipid metabolism especially for host-pathogen interaction, utilizing host lipids for energy and virulence. The rational approach is to target lipid metabolism of the pathogen focusing lipid-catabolizing lipases. The LdLip3 lipase is considered as drug target as it is constitutively expressed in both promastigote and amastigote forms. Since the LdLip3 structure is not known, we modeled its three-dimensional structure to implement structure-based drug discovery approach. Similarity-based virtual screening was carried out to identify potential inhibitors utilizing NCI diversity set on ZINC database including natural products. Implementing computational and experimental approaches, four anti-leishmanial agents were discovered. The screened molecules ZINC01821375, ZINC04008765, ZINC06117316 and ZINC12653571 had anti-leishmanial activity with IC50 (% viable promastigotes vs. concentration) of 5.2±1.8μM, 13.1±2.6μM, 9.4±2.6μM and 17.3±3.1μM, respectively. The molecules showed negligible toxicity toward mouse macrophages. Based on the contact footprinting analysis, new molecules were designed with better predicted free energy of binding than discovered anti-leishmanial agents. Further validation for the therapeutic utility of discovered molecules can be carried out by the research community to combat leishmaniasis.
authors: Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
authors: Saravanan
authors: S
authors: Parameswaran
authors: Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
authors: Prakash
authors: P
authors: Saudagar
authors: Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India.
authors: Vikash Kumar
authors: VK
authors: Dubey
authors: Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati 781039, Assam, India. Electronic address: sanjukta@iitg.ernet.in.
authors: Sanjukta
authors: S
authors: Patra
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects / Q000201:enzymology; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D050356:Lipid Metabolism; D051379:Mice; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D000981:Antiprotozoal Agents; D008049:Lipase
keywords: Homology modeling; Leishmaniasis; Lipase; Lipid metabolism; Structure-based drug discovery; Virtual screening