Computational Study of Novel Natural Inhibitors Targeting 3-Phosphoinositi-Dependent Protein Kinase 1(PDK1)

Abstract Objective To screen ideal lead compounds with potential inhibition of 3-phosphoinositi-dependent protein kinase 1 (PDK1) from ZINC15 database, which is beneficial to drug design and improvement.Methods The Discovery Studio 4.5 computer-aided virtual screening technique was used to screen potential inhibitors of PDK1. Libdock was used for virtual screening and scoring of candidate compounds, ADME module was used for physical and chemical properties and toxicity analysis, and CDOCKER module was used for molecular docking analysis. The binding affinity of ligand-PDK1 was studied through molecular docking, and the stability of ligand-PDK1 in the natural environment was analyzed through molecular dynamics simulation.Results Two natural compounds ZINC00000157721 and ZINC000034189841 were screened from ZINC15 database. These two compounds have no CYP2D6 inhibition, easy to pass the blood-brain barrier, no hepatotoxicity, high binding affinity with PDK1, higher stability in the natural environment than positive drug BX-795, and stable existence.Conclusions The results show that ZINC00000157721 and ZINC000034189841 are ideal and safe lead compounds and have a potential inhibitory effect on PDK1. These compounds are safe candidates and may provide the basis and premise for the design and optimization of specific PDK1 inhibitors.