Polypharmacology of Gongronema latifolium leaf secondary metabolites against protein kinases implicated in Parkinson's disease and Alzheimer's disease

Neurodegenerative diseases (NDD) are one of the major health concerns around the globe; Parkinson's disease (PD) and Alzheimer's disease (AD) are the most prevalent form of NDD. Protein kinases (PKs), common protein domains implicated in neurodegenerative diseases, are regulatory protein of cell functions; and play a pivotal role in signal transduction. Hence, this study considered the computational screening of secondary metabolites form Gongronema latifolium leaf for their inhibitory activities against the three prevalent PKs leucine-rich repeat kinase 2 (LRRK2), GSK3β (glycogen kinase 3β) and MAPK14 associated with the onset of AD and PD. The compounds were initially screened against LRRK2, GSK3β and MAPK14 by molecular docking to retrieve the hits. Nine (9) compounds were chosen and calculated for binding free energy to determine their stability with the proteins. The Lipinski, Ghose, Veber and Egan rules were considered to predict the compounds drug-likeness, in addition to drug-drug interaction and GI absorption. 2D QSAR models were constructed using a Kernel-based PLS regression model with Canvas binary fingerprint as the X variable. From the selected nine-hit with favourable stability with the proteins, 4 flavonoids (Catechin, Gallocatechin, Butein and Isorhamnetin) showed drug-likeness attributes with a low tendency for drug-drug interaction and high GI absorption. The generated QSAR models also predicted moderate pIC50 values for these compounds against the three PKs. This study will help in future endeavours for finding effective therapy for AD and PD.