Discovery of small molecule inhibitors of protein-protein interactions

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A receptor-based drug discovery approach can be applied when an accurate threedimensional (3D) structure of a specific PPI complex is available. A novel, complementary and transformative approach for the rational design of small molecule inhibitors based on the crystal structure of the p53-Mdm2 complex was developed. This method is based on a tight interplay of structural biology information, the “anchor” concept, efficient chemical synthesis via multicomponent reactions (MCRs), as well as virtual and real screening processes. Applying the method we efficiently discovered several new scaffolds of inhibitors of the p53/Mdm2 interaction with lower micromolar affinity binding to Mdm2, which can serve as starting point for medicinal chemistry optimization. Advantages of our approach include high hit rates and less attrition based on the parallel discovery of multiple scaffolds, built-in optimization pathways using efficient MCRs, and fast generation of potential lead compounds. Potential anticancer drug candidates were identified by biochemical assays, co-crystallization, cell based assays, as well as further preclinical evaluations (solubility, metabolism, pharmacokinetics, and xenograft studies).

A ligand-based drug discovery approach was explored since PPIs are critically dependent on “anchor” residues, which can serve as the pharmacophore model for small molecules. Multicomponent reactions were employed for design of novel scaffolds and DOS of drug-like compounds, since hit identification of PPI inhibitors via traditional approaches such as high throughput screening (HTS) is fundamentally limited by chemotypes present in the library collections. Novel and diverse scaffolds based on the privileged structures (1,4-benzodiazepines, 1,4-thienodiazepines) and “anchor” residues, which can be accessible from multicomponent reactions, were designed and synthesized. Compared with conventional methods, these approaches are advantageous to generate small molecules targeting PPIs in terms of efficiency, diversity, and economy.

In summary, the approaches described in this dissertation constitute important contributions to the fields of medicinal chemistry and structure-based drug discovery, which combine structural insights and ligand design to expedite the discovery of novel small molecule inhibitors of PPIs.