Insilico investigation of novel Plasmodium Falciparum Glycogen Synthase Kinase( pf GSk3β) inhibitors for the treatment of malaria infection

Abstract Figure

Malaria, a parasitic disease, remains a global health burden with over 260 million cases worldwide in 2023. With the increasing resistance to existing antimalarials, there is an increasing demand in the continuous search for novel therapeutic targets and strategies. Glycogen synthase kinase (pfGSKβ) is a key enzyme involved in metabolic processes such as glycogen synthase phosphorylation, cell differentiation and cell proliferation of the malaria parasite. An attempt to exploit this enzyme as a potential target for drug repurposing was investigated. The insilico method investigated in this research work involved the use of Python coding to mine data from the CHEMBL database for possible GSK3β inhibitors. The data mining using Python coding returned 53 potential molecules ranked according to their 1C50 value. The in silico analysis of these compounds using molecular docking, molecular dynamics simulations showed that three new molecules, labelledS20–CHEMBL ID 1910196 (4-[5-(6- hydroxy-1H-indol-2-yl)pyridin-3-yl]benzonitrile),S39- CHEMBL ID 2321945- (2-(7-bromo- 2-hydroxy-1H-indol-3-yl)-3-oxoindole-6-carboxylic acid) andS56-CHEMBL ID 2321951 (methyl 2-(2-hydroxy-1H-indol-3-yl)-3-nitroso-1H-indole-5-carboxylate), are potential molecules that can be used to inhibit pfGSK3β, of all these three molecules compoundS56were found to behave better insilico thanS1- (3,6-diamino-4-(2-chlorophenyl)thieno[2,3- b]pyridine-2,5-dicarbonitrile)-the co-crystallised ligand in pfGSK3β which was used as a control for the insilico drug repurposing research because it has already been tested to inhibit pfGSK3β, Finally, Protox III-an online webserver tool for insilico toxicity study was used to give the potential toxicity of the molecules, this will serve as a tool to guide further research in toxicity of the repurposed molecules. In conclusion, we have been able to propose that three new drug molecules,S39,S20andS56,have the potential of being repurposed for the treatment of Malaria infection.