Discovery of SBF1 as an allosteric inhibitor targeting the PIF-pocket of 3-phosphoinositide-dependent protein kinase-1

3-phosphoinositide-dependent protein kinase-1 (PDK1) plays a crucial role in the signal transduction of massive growth-related protein kinases. In this work, a computational study has been performed to investigate the binding pose of the hydrolyzed product of SBF1 (SBF1−) with PDK1. The binding pose was predicted by Vina and was further refined in a molecular dynamics simulation. For comparison, four published low molecular weight compounds (PS48, PS171, PS182, and PS210) binding with PDK1 were also studied. SBF1− was anchored in the PIF-pocket of PDK1 with salt bridge interaction using its carboxylate moiety, which is a common feature among the known ligands. Hydrogen bonds to THR148 and vdW interactions with GLN150 also have contributions to the association affinity. The allosteric regulation on PDK1 via the binding of SBF1− was further addressed. The binding affinity of SBF1− in complex with PDK1 is comparable to those of PS171 and PS182, with an estimated IC50 in a range from 2.0 to 10.0 μ molar. Comparison between the free energy profiles with the presence or absence of SBF1− in the binding pocket indicates that the binding of SBF1− enhances the hinge motion and suppresses the fluctuation of the end-to-end distance in α B of PDK1. These results demonstrate that SBF1− is a promising allosteric regulator of PDK1 targeting the PIF-binding pocket and can serve as a new scaffold template for the design of new drugs targeting PDK1.