Structure-based drug design and molecular dynamics studies of an allosteric modulator targeting the protein-protein interaction site of PDK1.

Context: Protein-protein interaction interfaces play a major role in cell signaling pathways. There is always a great interest in developing protein-protein interaction (PPI) inhibitors of kinases, as they are challenging due to their hydrophobicity, flat surface, specificity, potency, etc. 3 Phosphoinositide-dependent kinase-1 (PDK1), which is involved in the PI3K/PDK1/AKT pathway, is a cancer target that has gained insight for the past two decades.

Insilico design of an allosteric modulator targeting the protein-protein interaction site of 3 Phosphoinositide dependent Kinase-1: design, synthesis and biological activity.

Unlabelled: The signalling pathways in human cells mostly rely on protein-protein interactions (PPI) for their function. Such a PPI site in 3 Phosphoinositide dependent Kinase-1 (PDK1) is targeted to design the small molecule modulators. Based on the hotspot residues in its PPI site, a pharmacophore with seven different features was developed and screened against 2.