Exploring Different Drug Targets Responsible for the Inhibitory Activity of N, N′-Substituted Diamine Derivatives in Leishmania

The genome sequence of Leishmania has given rise to diverse novel drug targets, and their identification remains the first step in drug discovery. This study aims to identify the possible anti-leishmanicidal activity target(s) of N1, N4-[dibenzylbutane-4′,4″-(dioxymethylenebenzene)]-1,4-diamine from a plethora of pathways in kinetoplastids. The compound was docked using AutoDockTools-1.5.6 against eight co-crystallized proteins selected from the protein data bank, each representing important biosynthetic pathways. The evaluation of the best conformational protein–ligand poses showed that the N, N′-substituted diamine binds more efficiently to glyceraldehyde-3-phosphate dehydrogenase (G3PDH) (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 observed 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) or the pteridine synthase (TS) of the sterol, glyoxalase and trypanothione biosynthetic pathways. The efficient inhibition of G3PDH and PTR1 targets in Leishmania by N, N′-substituted diamine molecule provides more insights into understanding the mechanism of leishmanicidal activity.