Identification of potential inhibitors of cholinergic and β-secretase enzymes from phytochemicals derived from Gongronema latifolium Benth leaf: an integrated computational analysis

• Published in: Molecular diversity Vol. 28; no. 3; pp. 1305 - 1322
• Main Authors: Gyebi, Gideon Ampoma, Ogunyemi, Oludare M., Ibrahim, Ibrahim M., Ogunro, Olalekan B., Afolabi, Saheed O., Ojo, Rotimi J., Anyanwu, Gabriel O., El-Saber Batiha, Gaber, Adebayo, Joseph O.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2024; Springer Nature B.V
• Subjects: Acetylcholinesterase - chemistry; Acetylcholinesterase - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - chemistry; Amyloid Precursor Protein Secretases - metabolism; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Aspartic Acid Endopeptidases - metabolism; Biochemistry; Biomedical and Life Sciences; Butyrylcholinesterase - chemistry; Butyrylcholinesterase - metabolism; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Cluster analysis; Enzymes; Humans; Life Sciences; Molecular Docking Simulation; Molecular Dynamics Simulation; Organic Chemistry; Original Article; Pharmacy; Phytochemicals; Phytochemicals - chemistry; Phytochemicals - pharmacology; Plant Extracts - chemistry; Plant Extracts - pharmacology; Plant Leaves - chemistry; Polymer Sciences; Molecular dynamic simulation; Silymarin; Acetylcholinesterase; Butyrylcholinesterase; Neurodegenerative disorders; Molecular docking
• ISSN: 1381-1991; 1573-501X; 1573-501X
• DOI: 10.1007/s11030-023-10658-y

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 h AChE, h BChE and h BACE-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 h AChE, h BChE and h BACE-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.