How does Combinatorial Chemistry differ from Rational Drug Design?

Question

I stumbled on Vertex Pharmaceuticals - Wikipedia.

It was one of the first biotech firms to use an explicit strategy of rational drug design rather than combinatorial chemistry.

Then I looked up Combinatorial Chemistry. What is Combinatorial Chemistry

     Combinatorial chemistry is a laboratory technique in which millions of molecular constructions can be synthesized and tested for biological activity.  It has generated massive numbers of targeted molecules for testing and the developing techniques of high throughput screening has automated the screening process so larger numbers of biological assays can be done.  All this together has reduced the discovery-to-market time from what used to be 10-14 years to 5-8 years.

But this doesn't explain how Combinatorial Chemistry differs from Rational Drug Design? Isn't Combinatorial Chemistry rational too? Mustn't chemists pick reactants rationally? Even if she can't predict the products, she won't picked her reactants randomly.

Answer 1

From a medical point of view the problem in drug discovery is to find a compound that causes a desired outcome, not one that interacts with a specific target. For instance, if you want to reduce mortality due to infection with Covid, you have many strategies that may be pursued at the molecular level, from vaccination to interference with viral propagation to reduction of symptoms or boosting of the immune response.

The difference between a combinatorial strategy and a rational strategy is to a first approximation simple: in a combinatorial strategy compounds are tested for activity without immediate concern for how they bring about an outcome. There is no "a priori" information to guide compound selection other than the common properties of known drugs (as encoded eg by Lipinski's rules) and the ability to procure or synthesize compounds. Therefore the "rational" approach in this case is to create as large a library and to screen as many compounds as is reasonable given cost and time.

Rational drug design takes into consideration a molecular target (such as a protein) and perhaps the mechanism of action of a known lead compound and designs future potential drug compounds around that target and/or lead. That narrows the set of compounds under consideration reducing time and cost.

In general, the strategies of combinatorial and rational design are not mutually exclusive. It is typical to start a rational strategy after early leads have been identified some other way, say through combinatorial chemistry. It is also common to design a set of compounds during a stage in rational drug design using a combinatorial strategy applied to develop next generation leads from a starting compound.