神经退行性疾病,如阿尔茨海默病(AD),对经济和心理系统产生负面影响。对于AD,由于其复杂的病理生理学,仍然缺乏改变疾病的治疗方法和有希望的治疗方法。在这项研究中,我们计算筛选了针对三种已知的AD治疗靶蛋白的真菌代谢产物的天然数据库。最初,基于药效团的,药物相似性类别被用于筛查,它过滤了17,544种真菌代谢物中的14种(A-N)最佳命中。14个最佳命中分别与GSK-3β对接,NMDA受体,和BACE-1研究寻找多靶点抑制剂的潜力。我们发现化合物B,F,L有免疫毒性,而E,H,I,和J具有较高的LD50剂量(5000mg/kg)。在检查的代谢物中,发现Bisacremine-C(化合物I)是针对GSK-3β(ΔG:-8.7±0.2Kcal/mol,Ki:2.4×106M-1),NMDA(ΔG:-9.5±0.1Kcal/mol,Ki:9.2×106M-1),和BACE-1(ΔG:-9.1±0.2Kcal/mol,Ki:4.7×106M-1)。它与GSK-3β的亲和力高25倍,与NMDA的亲和力高6.3倍,与BACE-1的亲和力比它们的天然配体高9.04倍,分别。分子动力学模拟参数,如RMSD,RMSF,Rg,还有SASA,所有这些都证实了目标酶的整体结构在与Bisacremine-C结合后没有明显变化,并且配体在大部分模拟时间内以稳定的构象保持在结合腔内。GSK-3β-比沙草胺-C复合物最重要的疏水接触是与ILE62,VAL70,ALA83和LEU188,而GLN185对H键很重要。在疏水接触方面,TYR184和PHE246是最重要的,而SER180对NMDA-Bisacremine-C中的H键至关重要。THR232对于BACE-1-Bisacremine-C和ILE110产生的疏水触点中的H键是最关键的。本研究为进一步的实验验证和临床试验奠定了基础。
Neurodegenerative disorders, such as Alzheimer\'s disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal metabolites against three known therapeutic target proteins of AD. Initially, a pharmacophore-based, drug-likeness category was employed for screening, and it filtered the 14 (A-N) best hits out of 17,544 fungal metabolites. The 14 best hits were docked individually against GSK-3β, the NMDA receptor, and BACE-1 to investigate the potential of finding a multitarget inhibitor. We found that compounds B, F, and L were immuno-toxic, whereas E, H, I, and J had a higher LD50 dose (5000 mg/kg). Among the examined metabolites, the Bisacremine-C (compound I) was found to be the most active molecule against GSK-3β (ΔG: -8.7 ± 0.2 Kcal/mol, Ki: 2.4 × 106 M-1), NMDA (ΔG: -9.5 ± 0.1 Kcal/mol, Ki: 9.2 × 106 M-1), and BACE-1 (ΔG: -9.1 ± 0.2 Kcal/mol, Ki: 4.7 × 106 M-1). It showed a 25-fold higher affinity with GSK-3β, 6.3-fold higher affinity with NMDA, and 9.04-fold higher affinity with BACE-1 than their native ligands, respectively. Molecular dynamic simulation parameters, such as RMSD, RMSF, Rg, and SASA, all confirmed that the overall structures of the targeted enzymes did not change significantly after binding with Bisacremine-C, and the ligand remained inside the binding cavity in a stable conformation for most of the simulation time. The most significant hydrophobic contacts for the GSK-3β-Bisacremine-C complex are with ILE62, VAL70, ALA83, and LEU188, whereas GLN185 is significant for H-bonds. In terms of hydrophobic contacts, TYR184 and PHE246 are the most important, while SER180 is vital for H-bonds in NMDA-Bisacremine-C. THR232 is the most crucial for H-bonds in BACE-1-Bisacremine-C and ILE110-produced hydrophobic contacts. This study laid a foundation for further experimental validation and clinical trials regarding the biopotency of Bisacremine-C.