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There is an increasing interest in identifying disease-relevant PPI and developing the corresponding therapeutic agents. Historically the development of small-molecule PPI inhibitors has been associated with multiple challenges. The molecular complexity of PPIs involving large and flat interfaces and a lack of appropriate screening libraries that would match the structural requirements of the target protein made many early PPI-directed discovery programs fall short. Further advances in structural biology, identification of the “hot spot” regions provided a stronger basis for a rational design of small molecule modulators. That coincided with extensive analysis of the PPI-relevant chemical space and the development of several strategies for building PPI-focused chemical libraries. At Asinex we have developed a holistic approach for the enrichment of our screening libraries with novel chemotypes that would be beneficial for exploring multiple PPIs. That includes the creation of PPI privileged building blocks, fragments, and novel structurally sophisticated a-helix mimetic scaffolds, all enhanced by powerful methodologies for their convenient synthesis. An α-helix is the most common type of secondary structure in proteins. This structure is also quite compact, in contrast to other secondary structural elements, providing the opportunity for the design of drug-like molecules mimicking this important motif. Several α-helix mimetics molecules have proved to be useful for targeting therapeutically significant PPIs including notable examples of HDM2(HDM4) and the BCL-2 family inhibitors. Based on several in silico pharmacophore models, we designed and developed synthetic scaffolds that are able to reproduce the substitution geometry of an α-helical motif and display the residual groups toward the hot spot pockets. A pharmacophore search in our PPI/α-helix mimetic library revealed several promising hits that were further prioritized based on docking scoring algorithms.