A lot has been said about the residence time, or binding kinetics, of small molecules to their targets. Drug binding kinetics has gained increased attention in medicinal chemistry and pharmacology due to its potentially stronger correlation to in vivo efficacy of drugs relative to a drugs thermodynamic affinity for its target. Since this is a hot area of research, I think it’s natural to speculate about it. Let me share some thoughts.
Firstly, the notion that kinetics correlates to in vivo efficacy is an excessively generalizing statement. So let’s consider the specific cases for ligand binding, assuming equivalent thermodynamic affinity for any given set of drugs. First, let’s consider rapid on-off binding kinetics of a drug. Some drugs have physico-chemical properties which make them attach very rapidly to binding sites of proteins. Since it is a low energy process to bind, it is also a low energy process to dissociate from the binding site, and thus the drug is a “fast binder.” A drug which is a fast binder elicits its biological effect quickly as well. Theoretically, a fast binder is overall more susceptible to metabolism, excretion, and sequestering with various proteins in the body. I’ll discuss this aspect below.
Next, let’s consider a “slow-onset, long residence time” drug. These types of drugs require long periods of time before they can bind a protein due to the sophisticated, high energy process of drug attachment. Long residence time drugs represented about 25 % of FDA approved drugs in a past review, and more recently may account for up to 25 percent of FDA approved drugs. Long residence time drugs have the advantage of persistently modifying the protein which they bind to. Superficially, this would seem to be a great idea since a drug has biological effects predominately when bound to proteins. However, modifying the function of key proteins for extended periods of times can have disastrous effects, even though models of a disease would not suggest such an outcome. This effect is summarized in the phrase “target mediated toxicity” and is one major reason why long residence time inhibitors are not a good idea. Furthermore, the whole notion of a long residence time drug is entirely superseded by pharmacokinetics anyway. If a drug is clear rapidly from the body, it doesn’t matter how long it will bind to its target. Thus, binding kinetics really should not even be a discussion until a drug’s pharmacokinetic profile has been optimized first.
I greatly respect the scientists who have put their intellectual ideas out for the world to consider and criticize, and the same holds true for those who have studied drug binding kinetics. The failure of so many drugs in clinical trials begs the question what pharmaceutical companies are lacking in their research of potential drugs. Unfortunately, drug binding kinetics is not a remedy to this lack of knowledge, and in fact, it may distract from more fundamental research which is required to make a successful drug. Toxicity and lack of efficacy continue to plague clinical candidates, and these features are much more closely intertwined with the general pharmacokinetics of drug more than anything else. In summary, my feeling is that binding kinetics remain a detail that has differing levels of importance in drug design, unlike absorption or distribution which are always absolutely vital to drug efficacy. Even when drug binding kinetics are important, it’s certainly not a given that a “long residence time” drug is better for treating an illness than a kinetically “short residence time” drug.
