Insights of structure-based virtual screening and MPO-based SAR analysis of berberine-benzimidazole derivatives against Parkinson disease

Parkinson's disease (PD) is a progressive neurological condition that causes tremors, rigidity and postural instability. In addition, it can lead to complications such as constipation, orthostatic hypotension, and psychiatric disorders like depression and anxiety. Berberine is a natural alkaloid used in Chinese medicine, extracted from various plants such as Berberis vulgaris and Tinospora cordifolia. The compounds have been reported to possess therapeutic activities, including anti-Alzheimer's, anti-diabetic, anti-inflammatory, antiviral, antibacterial and, in the context of this study, anti-Parkinson's action. This study conducts a structure-based virtual screening of aryl-substituted berberine-benzimidazole derivatives (D1-7). Molecular docking and dynamics simulations are used to predict pharmacodynamics against monoamine oxidase B (MAOB), while multiparametric optimization (MPO) is used to predict pharmacokinetics to the Central Nervous System (CNS). The aim is to propose new alkaloids derived from berberine that can modulate the activity of MAOB receptors in treating PD. The simulations revealed that the D7 compound, which contains a dichlorophenyl group, exhibited a high affinity with MAOB, with an affinity energy of -10 kcal/mol. In contrast, the fluoro- and nitro- substituted compounds showed lower affinity. Structure-activity/property relationship (SAR/SPR) analysis suggest that the chloro-substituted derivatives are more lipophilic and form essentially hydrophobic interactions with the MAOB. This is corroborated by the dynamics simulations, which show that the MAOB-D7 complex is highly stable and allows for a synergistic effect associated with other anti-Parkinson drugs, further enhancing the inhibition of MAOB. Furthermore, pharmacokinetic predictions indicate that optimal levels of lipophilicity and polarity enhance high passive permeability (P-app = 1.7 x 10(-5) cm/s) and metabolic stability of the D7 derivative, leading to increased distribution in the CNS.