LIM激酶(LIMK)是参与肌动蛋白动力学调节的蛋白激酶家族。LIMK有两种同工型,即,LIMK1和LIMK2。LIMK1在神经元组织中大量表达。LIMK1在树突棘的降解中起着至关重要的作用,这对我们更高的大脑功能很重要,比如记忆和学习。抑制LIMK1可改善树突棘的大小和密度,并对阿尔茨海默病具有保护作用。在这项研究中,我们采用了基于配体的药物设计和分子建模方法来识别虚拟命中。使用PF-00477736的药理作用来筛选Zinc15化合物库。然后将识别的命中通过药物可能性和PAINS过滤器。Further,全面的对接和严格的分子动力学模拟研究提供了三个虚拟命中。,ZINC504485634、ZINC16940431和ZINC1091071。命中显示出比标准配体更好的对接得分,PF-00477736。发现对接评分为-8.85、-7.50和-7.68kcal/mol。这些命中在对接研究中表现出与靶标的最佳结合特性,血脑屏障通透性,在硅药代动力学和低预测毒性。由RamaswamyH.Sarma沟通。
LIM kinases (LIMKs) are a family of protein kinases involved in the regulation of actin dynamics. There are two isoforms of LIMKs i.e., LIMK1 and LIMK2. LIMK1 is expressed abundantly in neuronal tissues. LIMK1 plays an essential role in the degradation of dendritic spines, which are important for our higher brain functions, such as memory and learning. The inhibition of LIMK1 improves the size and density of dendritic spines and acts as a protective effect against Alzheimer\'s disease. In this study, we have adopted ligand-based drug design and molecular modelling methods to identify virtual hits. The pharmacophoric features of PF-00477736 were used to screen the Zinc15 compounds library. The identified hits were then passed through drug-likeliness and PAINS filters. Further, comprehensive docking and rigorous molecular dynamics simulation study afforded three virtual hits viz., ZINC504485634, ZINC16940431 and ZINC1091071. The hits showed a better docking score than the standard ligand, PF-00477736. The docking score was found to be -8.85, -7.50 and -7.68 kcal/mol. These hits exhibited optimal binding properties with the target in docking study, blood-brain barrier permeability, in silico pharmacokinetics and low predicted toxicity.Communicated by Ramaswamy H. Sarma.