DFT, ADME studies and evaluation of the binding with HSA and MAO-B inhibitory potential of protoberberine alkaloids from Guatteria friesiana: theoretical insights of promising candidates for the treatment of Parkinson's disease.

contextParkinson's disease is a chronic neurodegenerative condition that has no cure, characterized by the progressive degeneration of specific brain cells responsible for producing dopamine, a crucial neurotransmitter for controlling movement and muscle coordination. Parkinson's disease is estimated to affect around 1% of the world's population over the age of 60, but it can be diagnosed at younger ages. One of the treatment strategies for Parkinson's disease involves the use of drugs that aim to increase dopamine levels or simulate the action of dopamine in the brain. A class of commonly prescribed drugs are the so-called monoamine oxidase B (MAO-B) inhibitors due to the fact that this enzyme is responsible for metabolizing dopamine, thus reducing its levels in the brain. Studies have shown that berberine-derived alkaloids have the ability to selectively inhibit MAO-B activity, resulting in increased dopamine availability in the brain. In this context, berberine derivatives 13-hydroxy-discretinine and 7,8-dihydro-8-hydroxypalmatine, isolated from Guatteria friesiana, were evaluated via density functional theory followed by ADME studies, docking and molecular dynamic simulations with MAO-B, aiming to evaluate their anti-Parkinson potential, which have not been reported yet. Docking simulations with HSA were carried out aiming to evaluate the transport of these molecules through the circulatory system.

methodsThe 3D structures of the berberine-derived alkaloids were modeled via the DFT approach at B3LYP-D3(BJ)/6-311 + + G(2df, 2pd) theory level using Gaussian 09 software. Solvation free energies were determined through Truhlar's solvation model. MEP and ALIE maps were generated with Multiwfn software. Autodock Vina software was used for molecular docking simulations and analysis of the interactions in the binding sites. The 3D structure of MAO-B was obtained from the Protein Data Bank website under PDB code 2V5Z. For the interaction of studied alkaloids with human serum albumin (HSA) drug sites, 3D structures with PDB codes 2BXD, 2BXG, and 4L9K were used. Molecular dynamics simulations were carried out using GROMACS 2019.4 software, with the GROMOS 53A6 force field at 100 ns simulation time. The estimation of the ligand's binding free energies was obtained via molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method.