Computer Aided Discovery Of Limk1 Inhibitors

limkl is a serine/threonine protein kinase, which plays an important role in the assembly of actin cytoskeleton in the cytoplasm. It can promote cell growth and form the actin cytoskeleton for cell attachment, spreading, movement by accepting stimulation of extracellular signal. This study mainly uses the 3D-QSAR, molecular docking and molecular dynamics simulation methods to provide guidance for designing high potent and selective limkl inhibitors and study the effect of fluorine introduced on activity of limkl inhibitors.In the study of urea-based limkl inhibitors, the structure of inhibitors were divided into five parts. Then, the structural activity and selectivity relationship of the two models were summarized. The essential amino acid residues in Molecular docking mode were Ala353, Glu414, Ile416, His464, Asn465 and Leu467 and the Molecular dynamics simulation of 5ns was also performed. Finally, according to the above results, five urea-based derivatives were designed, synthesized and tested. The results showed that the activity and selectivity of these five new compounds were greatly improved. In the study of the effect of the introduction of fluorine atoms on the activity of Limkl inhibitors, the value of RMSD was about 3A could illustrate the docking system was stable. From the analysis of RMSF and binding free energy, it could conclude that the residue Gly346 and its fluctuation, the interactions of electricity and van der Waals were important for the binding of limkl and its inhibitors.