👤 Gideon A Gyebi

The use of Gongronema latifolium for the management of various forms of neurological disorders has generated a lot of interest in the need to further investigate its neurotherapeutic constituents. This work, therefore, focused on assessing the inhibitory potential of selected bioactive components derived from G. latifolium against key neurotherapeutic targets and oxidant species associated with neurodegeneration using in vitro analysis and biomolecular modelling. G. latifolium methanol extract (GLME), solvent partition, chromatographic fractions (A-F) of GLME and pregnane compounds (Iloneoside and marsectohexol) derived from fraction-B with the highest activity were investigated for in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase (MAO) inhibition in addition to their in vitro antioxidant activities. The interactions of iloneoside, marsectohexol, and reference drugs with human acetylcholinesterase, butyrylcholinesterase, and β-secretase (BACE-1) were further assessed using molecular docking, binding free energy calculations, cluster analysis, and molecular dynamics simulations. The GLME and fractions inhibited the activities of both acetylcholinesterase and butyrylcholinesterase in a dose-dependent manner. Iloneoside and marsectohexol exhibited in vitro concentration-dependent inhibitory activities against acetylcholinesterase (IC50 = 19.28, 184.9 µM, respectively) and butyrylcholinesterase (IC50 = 30.75, 43.4 µM, respectively). These compounds also possess ferric ion-reducing, hydroxyl, and superoxide radical-scavenging activities. Iloneoside had the highest docking scores of -9.8, -9.9 -9.4 Kcal for AChE, BChE, and BACE1, respectively. The stability of the interaction of the bioactive compounds with the catalytic residues of the protein targets was preserved in a 100 ns molecular dynamics simulation. Iloneoside, a rare pregnane glycoside, was identified as a neurotherapeutic constituent of G. latifolium leaf. Further studies are suggested to investigate the neurotherapeutic potential in animal models. Show less

Neurodegenerative disorders (NDDs) are associated with increased activities of the brain acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and β-secretase enzyme (BACE1). Inhibition of these enzymes affords therapeutic option for managing NDDs such as Alzheimer's disease (AD) and Parkinson's disease (PD). Although, Gongronema latifolium Benth (GL) has been widely documented in ethnopharmacological and scientific reports for the management of NDDs, there is paucity of information on its underlying mechanism and neurotherapeutic constituents. Herein, 152 previously reported Gongronema latifolium derived-phytochemicals (GLDP) were screened against hAChE, hBChE and hBACE-1 using molecular docking, molecular dynamics (MD) simulations, free energy of binding calculations and cluster analysis. The result of the computational analysis identified silymarin, alpha-amyrin and teraxeron with the highest binding energies (-12.3, -11.2, -10.5 Kcal/mol) for hAChE, hBChE and hBACE-1 respectively as compared with those of the reference inhibitors (-12.3, -9.8 and - 9.4 for donepezil, propidium and aminoquinoline compound respectively). These best docked phytochemicals were found to be orientated in the hydrophobic gorge where they interacted with the choline-binding pocket in the A-site and P-site of the cholinesterase and subsites S1, S3, S3' and flip (67-75) residues of the pocket of the BACE-1. The best docked phytochemicals complexed with the target proteins were stable in a 100 ns molecular dynamic simulation. The interactions with the catalytic residues were preserved during the simulation as observed from the MMGBSA decomposition and cluster analyses. The presence of these phytocompounds most notably silymarin, which demonstrated dual high binding tendencies to both cholinesterases, were identified as potential neurotherapeutics subject to further investigation. Show less