Department of Chemistry, Federal University of Amazonas (DQ-UFAM), Manaus, AM, 69080-900, Brazil.
Thushara, Neethinagar-64, Kollam, Kerala, India.
J Mol Model. 2023 Nov 1;29(11):353. doi: 10.1007/s00894-023-05756-5.
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.
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.
帕金森病是一种慢性神经退行性疾病，目前尚无治愈方法，其特征是负责产生多巴胺的特定脑细胞进行性退化，多巴胺是控制运动和肌肉协调的关键神经递质。帕金森病估计影响全球 60 岁以上人群的 1%左右，但也可在更年轻时被诊断出来。帕金森病的治疗策略之一是使用旨在增加多巴胺水平或模拟大脑中多巴胺作用的药物。由于这种酶负责代谢多巴胺，从而降低大脑中的多巴胺水平，因此通常开处方的一类药物是所谓的单胺氧化酶 B（MAO-B）抑制剂。研究表明，小檗碱衍生的生物碱具有选择性抑制 MAO-B 活性的能力，从而增加大脑中多巴胺的可用性。在这种情况下，从 Guatteria friesiana 中分离得到的小檗碱衍生物 13-羟基-离散小檗碱和 7,8-二氢-8-羟基巴马汀，通过密度泛函理论（DFT）进行了评估，随后进行了 ADME 研究、与 MAO-B 的对接和分子动力学模拟，旨在评估它们的抗帕金森病潜力，目前尚未有报道。进行了与 HSA 的对接模拟，旨在评估这些分子通过循环系统的转运。
使用 Gaussian 09 软件，通过 DFT 方法在 B3LYP-D3（BJ）/6-311++G（2df，2pd）理论水平上对小檗碱衍生的生物碱的 3D 结构进行建模。通过 Truhlar 的溶剂化模型确定溶剂化自由能。使用 Multiwfn 软件生成 MEP 和 ALIE 图谱。使用 Autodock Vina 软件进行分子对接模拟和分析结合部位的相互作用。MAO-B 的 3D 结构从 Protein Data Bank 网站上的 PDB 代码 2V5Z 获得。对于研究生物碱与人血清白蛋白（HSA）药物部位的相互作用，使用 PDB 代码 2BXD、2BXG 和 4L9K 的 3D 结构。使用 GROMACS 2019.4 软件进行分子动力学模拟，模拟时间为 100ns。通过分子力学泊松-玻尔兹曼表面积（MM-PBSA）方法估算配体的结合自由能。
