Kinetic Limits on Engineering Agonist Drugs

kinetic-limits-on drug-design-v1

There are many drugs that act as agonists ligands (L) which means they “turn on” their target receptor (RL) so that it induces its normal down-stream signalling. Examples of such drugs include: growth hormones, insulin, steroids and G-protein coupled Recetor(GCPR) ligands such as morphine (opiods), neurotransmitters and scent/aroma compounds. In general you can improve the potency (EC50) of these drugs by improve their binding dissociation constant (Kd) for their receptor (for more detail see post on the Hill Equation).

kinetic-limits-on drug-design-v1

The Kd is equal to the ratio of the complex dissassembly rate contant (koff) over the complex assembly rate constant (kon). In general, kon is a diffusion-controlled constant defined by how quickly the receptor and ligand find each other (and collide with the right geometry). As such, in general, you can only improving the potency of a drug/ligand ([EC50), by reducing reducing its koff. This makes sense because: the “tighter” your drug binds the less it will “fall off” the receptor.

Unfortunately, there is a limit to how far engineering the koff can improve your ligand potency (EC50). Once your ligand, binds so tightly that koff is less than the rate constants for downstream signalling(ksignal) (or receptor recycling/endocytosis (kendo) the EC50 becomes as constant which is approximately equal to ksigalling / kon. This “kinetic-limit” is a basic thermodynamic limit which has been defined to occur around 1-10 pM through extensive theoretical and experimental work on the drugs described above (see references below)



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