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Exploring Different Drug Targets Responsible for the Inhibitory Activity of N, N'-Substituted Diamine Derivative in Leishmania
* 1 , * 1 , * 1 , * 2 , * 1 , * 1, 3
1  Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria Nsukka, 410001 Enugu State, Nigeria
2  Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, 410001, Enugu State, Nigeria
3  Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Madonna University, Elele, Nigeria
Academic Editor: Marco Annunziata


The genome sequence of Leishmania has given rise to diverse novel drug targets and their identification remains the first step in drug discovery. The aim of the study is to identify the possible antileishmanicidal activity target(s) of N1,N4-[dibenzylbutane-4',4''-(dioxymethylenebenzene)]-1,4-diamine from plethora of pathways in kinetoplastids. The compound was docked using AutoDockTools-1.5.6 against 8 co-crystallized proteins selected from the protein data bank and representing important biosynthetic pathways. The results showed that the N, N'-substituted diamine binds more efficiently to the glyceraldehyde-3-phosphate dehydrogenase, GPDH (E = -8.97 Kcal/mol and Ki = 0.267 µM; Ki co-crystallized ligand = 19.39 µM) which is responsible for the conversion of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate, and pteridine reductase I, PTR1 (E = -8.75 Kcal/mol and Ki = 0.387 µM; Ki co-crystallized ligand = 60.56 µM) which reduces both pterins and folates to tetrahydrobiopterin and tetrahydrofolate respectively. Moderate binding activity by the ligand was obtained for the protein kinases, CDKs (E = -8.37 Kcal/mol and Ki = 0.729 µM; Ki co-crystallized ligand = 26.80 µM) and trypanothione reductase, TR (E = -8.57 Kcal/mol and Ki = 0.525 µM; Ki co-crystallized ligand = 174.68 µM) of the trypanothione biosynthetic pathway. With E > -7.35 Kcal/mol and Ki > 4.10 µM, the ligand appears to have no significant inhibition of the squalene synthase (SQS), lactoyl glutathione lyase (LGL) and pteridine synthase (TS) of the sterol, glyoxalase and trypanothione biosynthetic pathways. In conclusion, the efficient inhibition of GPDH and PTR1 targets in Leishmania by N, N-substituted diamine molecule provides more insights into understanding the mechanism of leishmanicidal activity.

Keywords: Kinetoplastid, Leishmania; glyceraldehyde-3-phosphate dehydrogenase; pteridine reductase; substituted diamine