title: Structure-based virtual screening, molecular docking, ADMET and molecular simulations to develop benzoxaborole analogs as potential inhibitor against Leishmania donovani trypanothione reductase.
abstract: Visceral leishmaniasis (VL) is the most fatal form of leishmaniasis and it affects 70 countries worldwide. Increasing drug resistant for antileishmanial drugs such as miltefosine, sodium stibogluconate and pentamidine has been reported in the VL endemic region. Amphotericin B has shown potential antileishmanial activity in different formulations but its cost of treatment and associated nephrotoxicity have limited its use by affected people living in the endemic zone. To control the VL infection in the affected countries, it is necessary to develop new antileishmanial compounds with high efficacy and negligible toxicity. Computer aided programs such as binding free energy estimation; ADMET prediction and molecular dynamics simulation can be used to investigate novel antileishmanial molecules in shorter duration. To develop antileishmanial lead molecule, we performed standard precision (SP) docking for 1160 benzoxaborole analogs along with reference inhibitors against trypanothione reductase of Leishmania parasite. Furthermore, extra precision (XP) docking, ADMET prediction, prime MM-GBSA was conducted over 115 ligands, showing better docking score than reference inhibitors to get potential antileishmanial compounds. Simultaneously, area under the curve (AUC) was estimated using ROC plot to validate the SP and XP docking protocol. Later on, two benzoxaborole analogs with best MM-GBSA ΔG-bind were subjected to molecular simulation and docking confirmation to ensure the ligand interaction with TR. The presented drug discovery based on computational study confirms that BOB27 can be used as a potential drug candidate and warrants further experimental investigation to fight against VL in endemic areas.
authors.affiliation: a Department of Biochemistry, School of Life Sciences , Central University of Rajasthan , Kishangarh , 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 , Maharashtra , India.
authors.forename: Bajarang Vasant
authors.initials: BV
authors.lastname: Kumbhar
authors.affiliation: c Department of Medicine , Institute of Medical Sciences, Banaras Hindu University , Varanasi , 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 , 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 , Rajasthan , India.
authors.forename: Vijay Kumar
authors.initials: VK
authors.lastname: Prajapati
mesh_terms: D000981:Antiprotozoal Agents / Q000737:chemistry* / Q000494:pharmacology*; D001896:Boron Compounds / Q000737:chemistry*; D003198:Computer Simulation; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry*; D007893:Leishmania donovani / Q000187:drug effects / Q000201:enzymology*; D007898:Leishmaniasis, Visceral / Q000469:parasitology / Q000517:prevention & control; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D000981:Antiprotozoal Agents; D001896:Boron Compounds; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase
keywords: Benzoxaborole; molecular docking; molecular dynamics; trypanothione reductase; visceral leishmaniasis