Drug–Target Interaction

Ordinary, healthy body function runs on a constant stream of biochemical processes. Metabolism breaks down the food we eat and harvests the released energy as ATP, while simultaneously building the biomolecules the body needs from whatever precursor molecules are available, using a small army of enzymes as catalysts. Cell signalling runs alongside it: receptor molecules sense changes in the surrounding environment and pass signals onward, triggering the cell's appropriate response. Both processes can be knocked off course -- by an outside factor such as a microorganism or a foreign chemical, or by a disorder arising in the body's own machinery -- and when that happens, medicines are taken to nudge the system back to normal. …

Every biochemical reaction inside a living cell runs on an enzyme catalyst, so keeping enzyme activity normal is essential to keeping the whole system running -- and, turned around, disabling a pathogen's enzyme is one of the most reliable ways medicine has of killing that pathogen.

Normally, a substrate molecule finds and binds an enzyme's active site through a set of weak interactions -- hydrogen bonds, van der Waals forces -- with the amino acids that line that pocket. If a drug molecule happens to be shaped enough like the natural substrate, it can occupy that same pocket instead, physically blocking the substrate from binding and shutting the enzyme down. Because the drug is competing directly with the substrate for the same site, this class of drug is called a competitive inhibitor.

The textbook example is the antibiotic sulphanilamide, whose structure closely mimics p-aminobenzoic acid (PABA) -- a molecule many bacteria need in order to biosynthesise the essential coenzyme folic acid. When sulphanilamide is administered, it competitively occupies the active site of dihydropteroate synthase (DHPS), the bacterial enzyme in the PABA-to-folic-acid pathway -- so the bacteria can no longer make folic acid, their growth is retarded, and they can eventually be killed outright. …

A second major class of drug target is the receptor -- a protein whose job is to trigger a response inside a cell when the right molecule docks onto it. Most receptors sit embedded in the cell membrane with their binding site facing outward, exposed on the cell's outer surface, where a chemical messenger (the compound that actually carries the message) can reach and dock into it. Docking transfers the message into the cell's interior. Each receptor is highly selective, recognising one particular chemical messenger far better than any other.

This selectivity is what a drug can exploit in two opposite directions. If the goal is to block a message, a drug that binds the receptor's site and inhibits its natural function is called an antagonist. If the goal is instead to switch the receptor ON in the absence of its usual messenger -- mimicking that messenger -- the drug is called an agonist.

Two worked examples make the distinction concrete. Adenosine, binding its own receptor, induces sleepiness; caffeine is an antagonist at that same adenosine receptor -- it occupies the site and inactivates it, which is exactly why caffeine produces wakefulness rather than sleep. Morphine, by contrast, is an agonist at opioid receptors: binding and activating them suppresses the neurotransmitters responsible for carrying pain signals, which is the basis of its use as a pain killer. …