Design of Potential Inhibitors of Pf5-ALAS in Liver Stage Plasmodium falciparum: A Sustainable Chemotherapeutic Approach to Address Antimalarial Resistance
Oluwadunni F. Elebiju, Gbolahan Oladipupo Oduselu, Temitope Aminat Ogunnupebi, Olayinka Oyewale AJANI, Ezekiel Femi Adebiyi · IOP Conference Series Earth and Environmental Science · 2024
Abstract Plasmodium falciparum delta-aminolevulinate synthase (Pf5-ALAS) is the first enzyme in the heme biosynthetic pathway, and it is a liver stage specific enzyme in the developmental stages of Plasmodium falciparum. 8-amino quinoline derivatives have been reported to be active against liver stage parasite and hence was used as a template in the design of 12 derivatives as sustainable chemotherapeutics that were screened in this study designed as potential inhibitors of Pf5-ALAS. The target was modelled due to the unavailability of its experimentally validated 3-dimensional (3D) structure. The binding energy of all 12 designed compounds ranged from -7.9 to -9.1 Kcal/mol which all performed better than primaquine a known inhibitor of liver stage malaria. All twelve designed compounds had comparatively good pharmacokinetic profiles and did not present a toxicity risk, according to in silico ADMET prediction. The position and presence of a functional group that introduces a synergistic impact and subsequently raises the binding energy are highlighted in the qualitative structural assessment of the top three hits. This might pave way to highly economical new antimalarial therapeutic for sustainability health and wellbeing in sub-Saharan Africa and beyond.