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.

CONTEXT: Parkinson'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. METHODS: The 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.

Spectroscopic investigation, vibrational assignments, HOMO-LUMO, NBO, MEP analysis and molecular docking studies of oxoaporphine alkaloid liriodenine.

A combined experimental and theoretical DFT study of the structural, vibrational and electronic properties of liriodenine is presented using B3LYP function with 6-311G (2d, p) basis set. The theoretical geometry optimization data were compared with the X-ray data for a similar structure in the associated literature, showing similar values. In addition, natural bond orbitals (NBOs), HOMO-LUMO energy gap, mapped molecular Electrostatic Potential (MEP) surface calculation, first and second order hyperpolarizabilities were also performed with the same calculation level. Theoretical UV spectrum agreed well with the measured experimental data, with transitions assigned. The molecular electrostatic potential map shows opposite potentials regions that forms hydrogen bonds that stabilize the dimeric form, which were confirmed by the close values related to the CO bond stretching between the dimeric form and the experimental IR spectra (1654cm-1 for the experimental, 1700cm-1 for the dimer form). Calculated HOMO/LUMO gaps shows the excitation energy for Liriodenine, justifying its stability and kinetics reaction. Molecular docking studies with Candida albicans dihydrofolate reductase (DHFR) and Candida albicans secreted aspartic protease (SAP) showed binding free energies values of -8.5 and -8.3kcal/mol, suggesting good affinity between the liriodenine and the target macromolecules.