Structure-Function Relationships for Drug Discovery

Good afternoon everyone!  I wanted to expound upon our last post by describing one of the main paradigms in biology and chemistry: that a molecules structure relates to its function.  From the last post I threw some doubt on this topic with a thought experiment that showed structures are not always optimized to a specific function.  Despite this, there are many instances in nature where a molecule fits perfectly into a specific target.  This could be, for instance, like the Biotin-Streptavidin bond we discussed before.  In fact, mimicking molecular shapes is a very important part of drug discovery.

Distinct protein shapes are often important targets for drug therapies.  Enzymes, those proteins that catalyze chemical processes, often have a particular binding pocket for a target.  Sometimes the target is a key component of a malignant microorganism, like the outer coating of a virus, bacterium, or fungus.  I have recently been studying a class of anti-fungal drugs that work by inhibiting an enzyme that produces a key fungal coat product: ergosterol.  These drugs were developed by using ergosterol as a “lead compound”.  Scientists started out by modifying ergosterol to develop molecules that get stuck in the enzymes inner binding pocket (see figure 1).  Because of its precise shape, the drug is able to form bonds with certain amino acids in the enzyme and it is limited in its ability to escape.  These types of drug discovery methods highlight why crystal structures of proteins are vitally important to drug companies.


Drug Inhibition


Adapted from:


Even though drug molecules can be designed with high affinity for specific molecules, this does not always completely define its function.  Ergosterol, for example, has a common analogue in mammalian cells: cholesterol.  For this reason, there can be some crossover between drugs that bind to ergosterol makers and drugs that bind to cholesterol makers.  Such crossover might lead to off-target, negative effects for humans.  This is an active area of research as of the time of writing this article. All of this is just one example of the challenges and concerns in developing effective inhibitor-drugs.  I will talk about lead compound development and how to develop them into effective drug compounds in future posts.  Thanks for reading!




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