Fig. 2. Small molecule fragments for generating high affinity hybrids. (a) Benzhydryl pyrrolidine group for targeting the fusicoccin A binding pocket in 14-3-3. pS = phosphoserine (b) N-aryl pyrrole moiety for interacting with the hydrophobic pocket of HIV-1 gp41. P26 = NNYTSLIHSLIEESQNQQEKNEQELL. βA = β-Alanine (c) Nanomolar thrombin inhibitor with an exocyclic hydroxymethyl-benzyl group which induced a new hydrophobic cavity in the protein binding pocket. βHPro = l-β-Homoproline. (d) Selective MC5R binding hybrid (K1 major) generated by stereoselective 1,3-dipolar cycloaddition. The diastereoisomer, K1 minor, was unable to bind to the target. NMePhe = N-methyl-l-phenylalanine. f = d-phenylalanine. In each case the small molecule component is highlighted in red.