Fig. 29.12 (a) In the crystal structure, the trimeric TNFα (green) binds to three identical subunits of the TNF receptor (brown). In a screening campagin and after some design cycles of medicinal chemistry optimization, the ligand 29.27 was obtained. It binds with micromolar affinity to the receptor in the dark and blocks the interaction of TNF with its receptor (b). Upon exposure to light, 29.27 reacts with the amide nitrogen of Ala 62 (c) and forms an irreversible covalent linkage. As a result, the inhibition becomes nanomolar. The low molecular weight ligand prevents formation of the TNF-receptor complex for steric reasons.