| Abstract
| - Five nonpeptide, small-molecule inhibitors of the human MDM2−p53 interaction are presented,and each inhibitor represents a new scaffold. The most potent compound exhibited a Ki of 110 ± 30 nM.These compounds were identified using our multiple protein structure (MPS) method which incorporatesprotein flexibility into a receptor-based pharmacophore model that identifies appropriate hotspots of binding.Docking the inhibitors with an induced-fit docking protocol suggested that the inhibitors mimicked the threecritical binding residues of p53 (Phe19, Trp23, and Leu26). Docking also predicted a new orientation ofthe scaffolds that more fully fills the binding cleft, enabling the inhibitors to take advantage of additionalhydrogen-bonding possibilities not explored by other small molecule inhibitors. One inhibitor in particularwas proposed to probe the hydrophobic core of the protein by taking advantage of the flexibility of thebinding cleft floor. These results show that the MPS technique is a promising advance for structure-baseddrug discovery and that the method can truly explore broad chemical space efficiently in the quest to discoverpotent, small-molecule inhibitors of protein−protein interactions. Our MPS technique is one of very fewensemble-based techniques to be proven through experimental verification of the discovery of new inhibitors.
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