Chapter 26

Fig. 26.20 (a) Binding mode of the substrate-analogous phosphotyrosine (26.39, Fig. 26.21) in human PTP-1B. The phosphate group binds deeply in the catalytic site (green). The two hydrophobic amino acids Phe182 and Tyr46 form a narrow entry portal to the catalytic center. A second phosphotyrosine (pink) is found in the crystal structure that binds to Arg24 and Arg254. (b) Crystal structure of an aromatic oxalic acid derivative (26.45) that was developed at Abbott to occupy the catalytic site (green). The compound induces a rearrangement of the Phe182 side chain and opens the catalytic site to the top. (c) By chemically coupling an aromatic carboxylic acid that was discovered with the SAR-by-NMR method as a binder for the second binding site (pink) and a mimetic to occupy the catalytic site, a nanomolar inhibitor 26.49 (Fig. 26.21) was obtained. (d) To achieve selective binding to PTP-1B compared to the structurally very similar TCPTP, structural differences at position 41 were exploited (light blue outlining). There PBP-1B has a lysine, and the related family member TCPTP has an Arg in this position. The nanomolar inhibitor 26.53 achieves a significant selectivity advantage.26.52 (light blue) binds with an uncharged head group into the catalytic center. The nanomolar inhibitor 26.51 (purple) also binds into the catalytic center but, like 24.49, it is oriented toward the second phosphotyrosine binding site (pink).