Annotated Library of MDM2-p53 Interaction Inhibitors

Annotated Library of MDM2-p53 Interaction Inhibitors

22,319 Compounds

Medicinal and Computational Chemistry Dept., ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121 USA, Service: +1 877 ChemDiv, Tel: +1 858-794-4860, Fax: +1 858-794-4931, Email: [email protected]

Introduction:
The p53 tumor suppressor protein is a transcriptional factor that plays a key role in regulation of several cellular processes, including the cell cycle, apoptosis, DNA repair, and angiogenesis. Activation of the p53 protein protects the organism against the propagation of cells that carry damaged DNA with potentially oncogenic mutations.
The MDM2 (murine double minute 2) oncogene is the primary cellular negative regulator of p53. In unstressed cells, a negative feedback loop maintains both p53 and MDM2 at very low levels. MDM2 is transcriptionally activated by p53, and the activity of p53 is regulated by MDM2 through three main mechanisms. First, MDM2 represses p53 transcriptional activity by binding to the p53 transactivation domain. Second, MDM2 transports p53 from the nucleus to the cytosol. Finally, MDM2 functions as an E3 ubiquitin ligase and facilitates the degradation of both p53 and itself in the cellular 26S proteasome.
The interaction between p53 and MDM2 is conformation-based and is tightly regulated on multiple levels. Disruption of the p53-MDM2 complex by multiple routes is the pivotal event for p53 activation, leading to p53 induction and its biological response. Because the p53-MDM2 interaction is structurally and biologically fairly understood, the design of small peptidomimetic molecules that disrupt or prevent it has become an important target for the treatment of cancer and other human diseases.
Major advances have been made in the design of small-molecule inhibitors of the MDM2-p53 interaction in recent years; several compounds have moved into preclinical and Phase I development.
Unfortunately, most of the known modulators of MDM2 have non-optimal physico-chemical properties and do not seem drug-like.
ChemDiv proposes the new library of drug-like MDM2-p53 interaction inhibitors; this library represents a selection of drug-like compounds aimed at modulating proteinprotein interaction (PPI) of MDM2 with protein p53 involved in tumorogenesis. The library has been assembled using ChemDiv’s in house structural biology insight, molecular stimulation-modeling, and virtual screening of ChemDiv’s novel chemistries and medicinal chemistry filtering/ranking of the resulting hits. A representative example of a ‘druggable’ ‘hot spot’ included specific topological features of the MDM2-p53 interaction. For example, the cocrystal structure reveals that three amino acid residues of p53 (Trp23, Leu26, and Phe19) are responsible for key hydrophobic contacts with the MDM2 protein. Furthermore, the cocrystal structures of known small molecules bound to MDM2 support the importance of targeting these three hydrophobic regions when attempting to disrupt the MDM2−p53 PPI.
ChemDiv combined a number of in silico screening approaches and specific spatial PPI information to design sub-libraries centered on a scaffolds that project side chain functionalities with distance and angular properties similar to those seen in the MDM2 interacting motif of p53.

Important Information Inspired the Library Design

Variable statistics for 8,838 compounds from MDM2 library.
Diversity 0,8064
The number of screens in dataset 2,197
Number of unique heterocycles 85
The number of Scaffolds 88
Singletons 8
Novelty: the number of compounds (%) per year

References:
1. Betzi, S; Morelli, X; Roche, P; Zhang, X. Focused chemical libraries – design and enrichment: an example of protein–protein interaction chemical space. Future Med. Chem. 2014, 6(11), 1291–1307.
2. Hamon, V.; Brunel, J. M.; Combes, S.; Basse, M.J.; Roche, P.; Morelli, X. 2P2Ichem: focused chemical libraries dedicated to orthosteric modulation of protein-protein interactions. MedChemComm. 2013, 10.1039/c3md00018d.
3. Hamon V et al. 2014. 2P2IHUNTER: a tool for filtering orthosteric protein– protein interaction modulators via a dedicated support vector machine. J. R. Soc. Interface 11: 20130860.http://dx.doi.org/10.1098/rsif.2013.0860

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