title: Screening natural products database for identification of potential antileishmanial chemotherapeutic agents.
abstract: Leishmaniasis is a parasitic infection caused by unicellular protozoan organism belonging to the family Trypanosomatidae. Among various forms of the disease, visceral leishmaniasis is the most lethal and caused by Leishmania infantum or Leishmania donovani. The redox metabolism of parasite requires a key enzyme, trypanothione reductase which is a validated drug target. In the past decade, it was observed that these protozoan parasites had developed resistance against many of available drugs. Importantly in the case of visceral leishmaniasis drug resistance is very high in the Indian subcontinent, a major endemic region of Leishmania donovani infection. In search for new drugs, we aim to identify potential natural product inhibitors of trypanothione reductase which can be further developed as anti-leishmanial drug. We have performed in silico virtual screening of a natural product data set of 800 diverse chemical entities. Leishmania infantum trypanothione reductase crystal structure (PDB ID: 2JK6) was used in the virtual screening process, docking studies to identify potential lead compounds. The compounds were sorted based upon their binding energy and the top 50 ranked protein-inhibitor complexes were clustered using AuPosSOM to ligand foot print the interactions. We report a few alkaloids and sterols for the first time, which could be potential trypanothione reductase inhibitors. The footprinting of protein-inhibitor interactions into clusters has also provided clues on various possible orientations that inhibitors can attain at the active site of Trypanothione reductase. Moreover, biological significance of the interactions has also been discussed.
authors.affiliation: Department of Biotechnology, Indian Institute of Technology Guwahati, Assam, 781039, India.
authors.forename: Santhosh K
authors.initials: SK
authors.lastname: Venkatesan
authors.forename: Prakash
authors.initials: P
authors.lastname: Saudagar
authors.forename: Anil K
authors.initials: AK
authors.lastname: Shukla
authors.forename: Vikash Kumar
authors.initials: VK
authors.lastname: Dubey
mesh_terms: D000981:Antiprotozoal Agents / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D001688:Biological Products / Q000032:analysis* / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D019992:Databases as Topic; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D007891:Leishmania / Q000187:drug effects*; D008024:Ligands; D008958:Models, Molecular
chemical_list: D000981:Antiprotozoal Agents; D001688:Biological Products; D008024:Ligands