title: Febrifugine analogues as Leishmania donovani trypanothione reductase inhibitors: binding energy analysis assisted by molecular docking, ADMET and molecular dynamics simulation.
abstract: Visceral leishmaniasis affects people from 70 countries worldwide, mostly from Indian, African and south American continent. The increasing resistance to antimonial, miltefosine and frequent toxicity of amphotericin B drives an urgent need to develop an antileishmanial drug with excellent efficacy and safety profile. In this study we have docked series of febrifugine analogues (n = 8813) against trypanothione reductase in three sequential docking modes. Extra precision docking resulted into 108 ligands showing better docking score as compared to two reference ligand. Furthermore, 108 febrifugine analogues and reference inhibitor clomipramine were subjected to ADMET, QikProp and molecular mechanics, the generalized born model and solvent accessibility study to ensure the toxicity caused by compounds and binding-free energy, respectively. Two best ligands (FFG7 and FFG2) qualifying above screening parameters were further subjected to molecular dynamics simulation. Conducting these studies, here we confirmed that 6-chloro-3-[3-(3-hydroxy-2-piperidyl)-2-oxo-propyl]-7-(4-pyridyl) quinazolin-4-one can be potential drug candidate to fight against Leishmania donovani parasites.
authors.affiliation: a 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: b Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Mumbai 400076 , Maharashtra , India.
authors.forename: Bajarang Vasant
authors.initials: BV
authors.lastname: Kumbhar
authors.affiliation: c Department of Pharmacy , School of Chemical Sciences, Central University of Rajasthan , Kishangarh 305817 , Ajmer, Rajasthan , India.
authors.forename: Shubham
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: c Department of Pharmacy , School of Chemical Sciences, Central University of Rajasthan , Kishangarh 305817 , Ajmer, Rajasthan , India.
authors.forename: Ruchi
authors.initials: R
authors.lastname: Malik
authors.affiliation: d Department of Medicine , Institute of Medical Sciences, Banaras Hindu University , Varanasi 221005 , Uttar Pradesh , India.
authors.forename: Shyam
authors.initials: S
authors.lastname: Sundar
authors.affiliation: b Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay , Mumbai 400076 , Maharashtra , India.
authors.forename: Ambarish
authors.initials: A
authors.lastname: Kunwar
authors.affiliation: a Department of Biochemistry , School of Life Sciences, Central University of Rajasthan , Kishangarh 305817 , Ajmer, Rajasthan , India.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Prajapati
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D007893:Leishmania donovani / Q000201:enzymology*; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D055503:Protein Multimerization; D011799:Quinazolines / Q000737:chemistry* / Q000494:pharmacology; D012372:ROC Curve; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D008024:Ligands; D010880:Piperidines; D011799:Quinazolines; C001207:febrifugine; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase
keywords: ROC curve; molecular docking; molecular dynamics; trypanothione reductase; visceral leishmaniasis