How do you approach allosteric drug design?

Allosteric drug design targets sites distinct from active sites, offering advantages: higher selectivity (allosteric sites are less conserved), ability to modulate rather than block activity, and reduced resistance development. Strategies include: computational site detection (FTMap, SiteMap, cavity analysis), fragment-based screening at identified pockets, HTS with functional readouts capturing modulation, and biochemical/biophysical characterization of hits (ITC, SPR, HDX-MS). Mechanistic characterization determines whether modulators are positive (PAM), negative (NAM), or neutral allosteric modulators. Structural studies (crystallography, cryo-EM) guide optimization. Challenges include: lower hit rates than orthosteric targeting, complex SAR, and species differences in allosteric sites. Success examples include HIV integrase allosteric inhibitors, GPCR allosteric modulators, and kinase type III inhibitors.