title: Developing imidazole analogues as potential inhibitor for Leishmania donovani trypanothione reductase: virtual screening, molecular docking, dynamics and ADMET approach.
abstract: Visceral leishmaniasis (VL) affects Indian subcontinent, African and South American continent, and it covers 70 countries worldwide. Visceral form of leishmaniasis is caused by Leishmania donovani in Indian subcontinent which is lethal if left untreated. Extensive resistance to antileishmanial drugs such as sodium stibogluconate, pentamidine and miltefosine and their decreased efficacy has been reported in the endemic region. Amphotericin B drug has shown good antileishmanial activity with significant toxicity, but its cost of treatment has limited the outreach of this treatment to affected people living in endemic zone. So, there is an urgent need to identify new antileishmanial drugs with excellent activity and minimal toxicity issues. Trypanothione reductase, a component of antioxidant system, is necessary for parasite growth and survival to raise infection. To develop potential inhibitor, we docked nine hundred and eighty-four 5-nitroimidazole analogues along with clomipramine which is a well-known inhibitor for TR. Total one hundred and forty-seven 5-nitroimidazole analogues with better docking score than clomipramine were chosen for ADMET and QikProp studies. Among these imidazole analogues, total twenty-four imidazole analogues and clomipramine were chosen on the basis of their ADMET, QikProp, and prime MM-GBSA study. Later on, two analogues with best MM-GBSA dG bind were undergone molecular dynamic simulation to ensure protein-ligand interactions. Using above approach, we confirm that ethyl 2-acetyl-5-[4-butyl-2-(3-hydroxypentyl)-5-nitro-1H-imidazol-1-yl]pent-2-enoate can be a drug candidate against L. donovani for the treatment of VL in the Indian subcontinent.
authors: a Department of Biochemistry , School of Life Sciences, Central University of Rajasthan , Kishangarh 305817 , Ajmer , Rajasthan , India.
authors: Rajan Kumar
authors: RK
authors: Pandey
authors: b Department of Biotechnology , School of Life Sciences, Central University of Rajasthan , Kishangarh 305817 , Ajmer , Rajasthan , India.
authors: Drista
authors: D
authors: Sharma
authors: b Department of Biotechnology , School of Life Sciences, Central University of Rajasthan , Kishangarh 305817 , Ajmer , Rajasthan , India.
authors: Tarun Kumar
authors: TK
authors: Bhatt
authors: c Department of Medicine , Institute of Medical Sciences, Banaras Hindu University , Varanasi 221005 , UP , India.
authors: Shyam
authors: S
authors: Sundar
authors: a Department of Biochemistry , School of Life Sciences, Central University of Rajasthan , Kishangarh 305817 , Ajmer , Rajasthan , India.
authors: Vijay Kumar
authors: VK
authors: Prajapati
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006790:Host-Parasite Interactions / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D007893:Leishmania donovani / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D007898:Leishmaniasis, Visceral / Q000469:parasitology / Q000517:prevention & control; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D010421:Pentanoic Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008024:Ligands; D010421:Pentanoic Acids; D015800:Protozoan Proteins; C000611674:ethyl 2-acetyl-5-(4-butyl-2-(3-hydroxypentyl)-5-nitro-1H-imidazol-1-yl)pent-2-enoate; C029899:imidazole; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase
keywords: Leishmaniasis; imidazole; molecular docking; molecular dynamics; trypanothione reductase