Small molecule inhibitors of the MDM2-p53 interaction discovered by ensemble-based receptor models.
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 incorporates protein 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 three critical binding residues of p53 (Phe19, Trp23, and Leu26). Docking also predicted a new orientation of the scaffolds that more fully fills the binding cleft, enabling the inhibitors to take advantage of additional hydrogen-bonding possibilities not explored by other small molecule inhibitors. One inhibitor in particular was proposed to probe the hydrophobic core of the protein by taking advantage of the flexibility of the binding cleft floor. These results show that the MPS technique is a promising advance for structure-based drug discovery and that the method can truly explore broad chemical space efficiently in the quest to discover potent, small-molecule inhibitors of protein-protein interactions. Our MPS technique is one of very few ensemble-based techniques to be proven through experimental verification of the discovery of new inhibitors.
Bowman
Anna L
AL
Department of Medicinal Chemistry and the Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Nikolovska-Coleska
Zaneta
Z
Zhong
Haizhen
H
Wang
Shaomeng
S
Carlson
Heather A
HA
D001667:Binding, Competitive; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008968:Molecular Conformation; D016011:Normal Distribution; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012984:Software; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D010455:Peptides; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2