Covid-19被宣布为世界大流行。最近的研究表明,Covid-19通过穿越血脑屏障和随之而来的认知障碍来损害中枢神经系统的活动。在这项研究中,我们利用Covid-19主蛋白酶(Mpro)作为生物学靶标,重新利用我们先前报道的针对阿尔茨海默病的多功能化合物。分子对接,空间取向,分子动力学模拟,MM-GBSA能量计算,用这些分子进行DFT研究。在所有的化合物中,F27,F44和F56表现出更高的结合能(-8.03,-8.65和-8.68kcal/mol,分别)在共晶配体O6K(-7.00kcal/mol)上。在MD模拟中,化合物F27、F44和F56可以在整个模拟过程中与Mpro靶标形成稳定的复合物。这些化合物是按照报道的方法合成的,并进行细胞毒性,并在PAMPA测定中评估它们穿过血脑屏障的能力,并通过DPPH测定进行抗氧化性能评价。化合物F27,F44和F56表现出与SiHA细胞系的细胞相容性,并且还表现出明显的抗氧化特性,IC50=45.80±0.27μM,44.42±0.30μM,和42.74±0.23μM。在PAMPA检测中,F27、F44和F56的渗透系数(Pe)值在可接受的范围内(Pe>4)。计算和初步体外研究的结果有力地证实了F27、F44和F56作为进一步优化与新冠肺炎相关的中枢神经系统并发症治疗的潜在线索。
Covid-19 was declared a world pandemic. Recent studies demonstrated that Covid-19 impairs CNS activity by crossing the blood-brain barrier and ensuing cognitive impairment. In this study, we have utilized Covid-19 main protease (Mpro) as a biological target to repurpose our previously reported multifunctional compounds targeting Alzheimer\'s disease. Molecular docking, spatial orientation, molecular dynamics simulation, MM-GBSA energy calculation, and DFT studies were carried out with these molecules. Among all the compounds, F27, F44, and F56 exhibited higher binding energy (- 8.03, - 8.65, and - 8.68 kcal/mol, respectively) over the co-crystal ligand O6K (- 7.00 kcal/mol). In MD simulation, compounds F27, F44, and F56 could make a stable complex with Mpro target throughout the simulation. The compounds were synthesized following reported methods and subjected for cytotoxicity, and assessment of their capability to cross the blood-brain barrier in
PAMPA assay, and antioxidant property evaluation through DPPH assay. The compounds F27, F44, and F56 exhibited cytocompatibility with the SiHA cell line and also displayed significant antioxidant properties with IC50 = 45.80 ± 0.27 μM, 44.42 ± 0.30 μM, and 42.74 ± 0.23 μM respectively. In the
PAMPA assays, the permeability coefficient (Pe) value of F27, F44, and F56 lies in the acceptable range (Pe > 4). The results of the computational and preliminary in-vitro studies strongly corroborate the potential of F27, F44, and F56 as a lead for further optimization in treating the CNS complications associated with Covid-19.