Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences, Ardabil, Iran.
Department of Medicinal Chemistry, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran.
Comput Biol Chem. 2018 Dec;77:307-317. doi: 10.1016/j.compbiolchem.2018.10.015. Epub 2018 Nov 1.
Increasing evidence suggests the beneficial impact of flavonoid-rich nutrition on normal cognitive function. It has been revealed that flavonoids can slow neurodegenerative processes in situations such as Alzheimer's disease (AD). The β-secretase (BACE-1) is one of the most studied targets in AD therapy owing to its role in producing Aβ plaques. In fact the unique role of BACE-1 in pathogenesis of neurodegenerative diseases has made it a druggable target to develop anti-AD agents. Taking into account the anti-amyloidogenic and anti-oxidative properties, flavonoids have received considerable attention as lead candidates for anti-AD drug discovery projects. In continuation to our interest toward rational exploration of potential anti-AD agents, it was attempted to conduct a combined structure based in silico study and explore pharmacophore of a flavanocoumarin derivative as BACE-1 Inhibitor. Ab initio studies showed that both pseudo-axial and pseudo-equatorial conformers could convert to each other freely at room temperature. Within this study it was revealed that artoflavanocoumarin possess essential pharmacophoric groups to inhibit BACE-1. Considering four different protonation states of BACE-1 as di-deprotonated, diprotonated, protonated Asp32 and protonated Asp228, it was also found that affinity of artoflavanocoumarin toward different protonation states of BACE-1could be ranked as Asp32p-Asp228i > di-deprotonated ∼ Asp32i-Asp228p >> diprotonated. PMF study on artoflavanocoumarin showed that it could pass 1.8 kcal/mol free energy barrier from water to DPPC lipid bilayer. Moreover the pros and cons of artoflavanocoumarin as a lead compound were elucidated.
越来越多的证据表明，富含类黄酮的营养物质对正常认知功能有益。已经发现，类黄酮可以减缓阿尔茨海默病（AD）等情况下的神经退行性过程。β-分泌酶（BACE-1）是 AD 治疗中研究最多的靶点之一，因为它在产生 Aβ斑块方面发挥作用。事实上，BACE-1 在神经退行性疾病发病机制中的独特作用使其成为开发抗 AD 药物的可药用靶点。考虑到抗淀粉样变性和抗氧化特性，类黄酮作为抗 AD 药物发现项目的潜在先导候选物受到了相当多的关注。继我们对潜在抗 AD 药物的合理探索兴趣之后，我们试图进行一项基于结构的计算机模拟联合研究，并探索作为 BACE-1 抑制剂的 flavanocoumarin 衍生物的药效团。从头算研究表明，在室温下，假轴向和假赤道构象都可以自由相互转化。在这项研究中，发现 artflavanocoumarin 具有抑制 BACE-1 的必需药效团。考虑到 BACE-1 的四种不同质子化状态，即双去质子化、双质子化、质子化的 Asp32 和质子化的 Asp228，还发现 artflavanocoumarin 与 BACE-1 的不同质子化状态的亲和力可以排序为 Asp32p-Asp228i > di-deprotonated∼Asp32i-Asp228p >> diprotonated。artflavanocoumarin 的 PMF 研究表明，它可以从水中通过 1.8 kcal/mol 的自由能屏障进入 DPPC 脂质双层。此外，还阐明了 artflavanocoumarin 作为先导化合物的优缺点。
