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3-Phosphoinositide-dependent kinase-1 (PDK1) plays a key role in the regulation of physiological processes and its catalytic activity is tightly regulated by allosteric modulators which bind to the PDK1 Interacting Fragment (PIF) pocket. However, details on the allosteric modulators regulation of the PDK1 catalytic activity remain elusive. Here, molecular docking and molecular dynamics (MD) simulations were performed to investigate the allosteric regulation of PDK1 induced by one of the benzoazepin-2-ones, the most potent compound 17 (BAZ2O). Molecular docking and MD simulation revealed that BAZ2O was located in the PIF pocket formed by residues from β4 and β5 sheets and helices αB and αC. BAZ2O formed a hydrogen bond with Arg131 and participated in hydrophobic interactions with Ile119, Thr148, Gln150, Leu155 and Phe157. Further comparative analyses of PDK1 in its apo and BAZ2O-bound states unveiled that BAZ2O promoted the structural coupling between the important catalytic domains of PDK1, including the activation loop and the helices αB and αC, thereby stabilizing the PDK1 conformation for catalysis. Understanding the allosteric interaction of PDK1 with small molecules provides a potentially valuable possibility of designing more potent allosteric modulators with therapeutic implications for lung cancer.

Computational insights into allosteric interaction between benzoazepin-2-ones and lung cancer-associated PDK1: Implications for activator design