Why Does a Chemical Library Favor Some Proteins?

Ian Quigley says chemical library design depends on the building blocks, a whole library made in one geometry might be really good for some types of protein targets and really crappy for other types, and some corners of chemical space are probably weak. The spread is in how the library performs across target types.

A design is usually limited to two or three building blocks stitched together. One design run a lot right now is a forked, Y-shaped molecule. Other choices are linear molecules and circular, macrocycle-shaped ones. DNA has to sit somewhere on the molecule, and that placement can cause problems. Commercial availability of building blocks and the chemistries required to stitch them together decide what is practical. Custom blocks are possible and take longer, so going faster is more appealing.

Future libraries should take on the geometry the weak corners need. The open tension is which corners of protein space to optimize for when different proteins get thrown at the library.