ABSTRACT
The binding conformations of α-helical hydrophobic hot spots are convergent into two spatial areas in protein-protein complex structures. The physical basis for convergence was disclosed, which allows the development of pharmacophore models for i/i + 4/i + 7 or i/i + 3/i + 4 α-helical hot spots. Further investigation revealed that this convergence of binding conformations is common among all hydrophobic hot spots regardless of their α-helical positions. This observation led to a streamlined generation of pharmacophore models for hydrophobic hot spots at any positions along the α-helix. These successfully evaluated pharmacophore models may be useful for designing novel α-helical hot spot mimetics.
ABSTRACT
Fragment-based ligand discovery (FBLD) is one of the most successful approaches to designing small-molecule protein-protein interaction (PPI) inhibitors. The incorporation of computational tools to FBLD allows the exploration of chemical space in a time- and cost-efficient manner. Herein, a computational protocol for the development of small-molecule PPI inhibitors using fragment hopping, a fragment-based de novo design approach, is described and a case study is presented to illustrate the efficiency of this protocol. Fragment hopping facilitates the design of PPI inhibitors from scratch solely based on key binding features in the PPI complex structure. This approach is an open system that enables the inclusion of different state-of-the-art programs and softwares to improve its performances.
