In-silico evaluations of the isolated phytosterols from polygonum hydropiper L against BACE1 and MAO drug targets

Abstract

Our previous anti-Alzheimer's studies on crude extracts, essential oils and isolated compounds including β-sitostrol from Polygonum hydropiper L, motivated us for further studies against beta amyloid cleaving enzyme 1 (BACE1) and monoamine oxidases (MAO-A), (MAO-B) enzymes. Before performing detailed studies on the compounds using animal models and immunohistochemistry, molecular docking study was performed against three vital enzymes implicated in several neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), depression and anxiety to predict their inhibitory potential against important enzymes. Beta amyloid cleaving enzyme 1 (BACE1) is important enzyme that catalyze pathological amyloidogenic pathway of processing amyloid precursor proteins to form neurotoxic amyloid plaques. Subsequently, BACE1 inhibitors are considered an important tool in the management of AD. MAOs have been categorized in two well-known groups MAO-A and MAO-B, based on their differential affinity for various monoamines substrates. MAO-A has more affinity for norepinephrine and 5-HT, whereas, MAO-B mainly catalyze the breakdown of dopamine and 2-phenylathylamine (PEA) and other monoamines. Subsequently, they have divergent behavioral outcomes and play a significant role in pathophysiology of several neurodegenerative disorders like AD, depression, drug abuse, migraines, schizophrenia, Attention Deficit Disorder (ADD) and Parkinson’s disease (PD). Molecular docking was carried out to predict the binding modes of β-sitosterol and stigmasterol in the binding pockets of BACE1 (beta-sectretase 1) and MAO (monoamine oxidase A, B) enzymes. The 3 D structure of BACE1 (PDB ID: 2QP8), MAO A (PDB ID: 2ZPX) and MAO B (PDB ID: 2XFN) were downloaded from protein databank. The 3 D structures were then subjected to protonation and energy minimization using default parameters of MOE. Three dimensional structures of β-sitosterol and stigmasterol were built by using Molecular Builder Module program implemented in MOE and saved as a (.mdb) file for molecular docking. Subsequently, the energy of both the compounds were minimized up to 0.05 Gradient using MMFF 94 s force field implemented in MOE. Both the compounds were docked into the active site of proteins using the Triangular Matching docking method (default) and 10 different conformations for each compound were generated. To obtain minimum energy structures the ligands were allowed to be flexible during docking. At the end of docking, the predicted ligand-protein complexes were analyzed for molecular interactions. Overall the docking results showed that these compounds showed good interaction with active site residues of BACE1 as compare to MAO-A and MAO-B. Furthermore, β-sitosterol showed good interaction with BACE1 as compare to stigmasterol. Communicated by Ramaswamy H. Sarma