Characterization of Hydrophilic α‑Helical Hot Spots on the Protein–Protein Interaction Interfaces for the Design of α‑Helix Mimetics

The
cooperativity index, Kc, was developed
to examine the binding synergy between hot spots of the ligand–protein.
For the first time, the convergence of the side-chain spatial arrangements
of hydrophilic α-helical hot spots Thr, Tyr, Asp, Asn, Ser,
Cys, and His in protein–protein interaction (PPI) complex structures
was disclosed and quantified by developing novel clustering models.
In-depth analyses revealed the driving force for the protein–protein
binding conformation convergence of hydrophilic α-helical hot
spots. This observation allows deriving pharmacophore models to design
new mimetics for hydrophilic α-helical hot spots. A computational
protocol was developed to search amino acid analogues and small-molecule
mimetics for each hydrophilic α-helical hot spot. As a pilot
study, diverse building blocks of commercially available nonstandard
L-type α-amino acids and the phenyl ring-containing small-molecule
fragments were obtained, which serve as a fragment collection to mimic
hydrophilic α-helical hot spots for the improvement of binding
affinity, selectivity, physicochemical properties, and synthesis accessibility
of α-helix mimetics.