title: High-throughput virtual screening and quantum mechanics approach to develop imipramine analogues as leads against trypanothione reductase of leishmania.
abstract: Visceral leishmaniasis (VL) has been considered as one of the most fatal form of leishmaniasis which affects 70 countries worldwide. Increased drug resistance in Indian subcontinent urged the need of new antileishmanial compounds with high efficacy and negligible toxicity. Imipramine compounds have shown impressive antileishmanial activity. To find out most potent analogue from imipramine series and explore the inhibitory activity of imipramine, we docked imipramine analogues (n=93,328) against trypanothione reductase in three sequential modes. Furthermore, 98 ligands having better docking score than reference ligand were subjected to ADME and toxicity, binding energy calculation and docking validation. Finally, Molecular dynamic and single point energy was estimated for best two ligands. This study uncovers the inhibitory activity of imipramine against Leishmania parasites.
authors.affiliation: Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Kishangarh 305817, Ajmer, Rajasthan, India.
authors.forename: Rajan Kumar
authors.initials: RK
authors.lastname: Pandey
authors.affiliation: Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Kishangarh 305817, Ajmer, Rajasthan, India.
authors.forename: Parmila
authors.initials: P
authors.lastname: Verma
authors.affiliation: Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Kishangarh 305817, Ajmer, Rajasthan, India.
authors.forename: Drista
authors.initials: D
authors.lastname: Sharma
authors.affiliation: Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Kishangarh 305817, Ajmer, Rajasthan, India.
authors.forename: Tarun Kumar
authors.initials: TK
authors.lastname: Bhatt
authors.affiliation: Department of Medicine, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005, UP, India.
authors.forename: Shyam
authors.initials: S
authors.lastname: Sundar
authors.affiliation: Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Kishangarh 305817, Ajmer, Rajasthan, India. Electronic address: vkprajapati@curaj.ac.in.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Prajapati
mesh_terms: D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D007099:Imipramine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D007891:Leishmania / Q000187:drug effects / Q000201:enzymology*; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011789:Quantum Theory; D015203:Reproducibility of Results; D012997:Solvents; D013816:Thermodynamics
chemical_list: D008024:Ligands; D012997:Solvents; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D007099:Imipramine
keywords: ADMET; Imipramine; Molecular dynamics; Trypanothione reductase; Visceral leishmaniasis