Revisiting stromelysin inhibitors Background: Fragment based drug discovery involves screening for small, weakly active compounds in an assay and then tethering them together to form hit‐level compound. Instructions: Read the passage below concerning a fragment based search for inhibitors of stromelysin, a topic that was first presented in Chapter 9. Use the ideas in the passage to answer the questions that follow. Learning Goal: To understand better the types of molecules used as fragments and how hits are generated from the fragments. Back in Chapter 9 we discussed the development of stromelysin inhibitors to highlight the relationship between binding energies and the structure of a molecule. As it so happens, the stromelysin study is also an example of fragment based drug discovery. The study started with two fragments that were found to bind to stromelysin. One was acetohydroxamic acid (1) and the other was 4‐hydroxybiphenyl (2). Note that both are small, fragment‐sized molecules and have weak Ki values close to 1 mM and binding energies of −2.4 and −4.8 kcal/mol, respectively.
The fragments were then joined together. In this particular study, the binding sites for 1 and 2 were known to be close together and the approximate orientations of the two fragments were also known. These two details greatly helped the research team in designing tethers to connect the two fragments. The team reported four different tethers through the addition of between one and four CH2 units.
The discussion becomes more complicated because the activities are reported as IC50 values instead of Ki values. Through the Cheng‐Prussoff equation, if we know the concentration of the substrate