Unfortunately, when you select a molecule for binding to a certain receptor you are generally choosing molecules that easily bind in general, which often leads to off-target effects where other receptors are also affected.
Directed evolution of synthetic ligands is my research area. We can and do select for specificity as well as sensitivity.
It’s easier than you might think to select against “good general binders.” If a ligand has high affinity to a wide range of molecules, then you can use any of a wide range of molecules in your negative selection.
What’s harder is to select for specificity to just one of two structurally similar binding sites.
No :) I’m saying that the epitope the ligand binds may have bioactive analogs on other proteins in sites accessible to the ligand. This is where off-target binding mostly comes from, and it’s hard to prevent.
Contrast this with a ligand being good at “binding things in general,” ie without regard to structure. This problem is relatively easy to prevent.
Directed evolution of synthetic ligands is my research area. We can and do select for specificity as well as sensitivity.
It’s easier than you might think to select against “good general binders.” If a ligand has high affinity to a wide range of molecules, then you can use any of a wide range of molecules in your negative selection.
What’s harder is to select for specificity to just one of two structurally similar binding sites.
It’s been more than a decade since I was at university, so it’s plausible that I’m not up to date anymore on how ligands get chosen.
Is the claim that you are making that ligands that are chosen as drug candidates these days generally don’t bind anything off-target?
No :) I’m saying that the epitope the ligand binds may have bioactive analogs on other proteins in sites accessible to the ligand. This is where off-target binding mostly comes from, and it’s hard to prevent.
Contrast this with a ligand being good at “binding things in general,” ie without regard to structure. This problem is relatively easy to prevent.