No need to optimize plasma protein binding in drug design

It’s commonly accepted that only unbound drug molecules are available to interact with their targets. Therefore, it is a goal to increase in vivo unbound drug concentration by lowering plasma protein binding (PPB). In contrast to this common belief, Genentech’s scientists suggest that PPB is neither a good nor a bad property for a drug and should not be optimized in drug design[1]. They conclude:

Low PPB does not necessarily lead to high in vivo unbound plasma concentration. Instead, low intrinsic clearance leads to high in vivo unbound plasma concentration, and low efflux transport activity at the blood-brain barrier leads to high unbound brain concentration.

Statistics show that the PPB of 45% 2003-2013 new drugs is > 95% and the PPB of 24% is > 99%. Compounds with very high PPB (> 99%) can still be valuable drugs. If we had set a cut-off value for the PPB in drug design, we could have missed them.

Although no need to specifically optimize PPB, these parameters are important. Potency in a cell based assay is always worse than the potency in a protein based biochemical assay. A main reason for “shift of potency” is the difference in PPB. Of course, cell membrane permeability, membrane drug transport, and endogenous ligand concentrations are all suspects.

[1] J Med Chem. 2014, doi: 10.1021/jm5007935.