Structure-Activity Relationships

As you've probably noticed by now, I've changed the background of my blog a bit to *hopefully* make it easier to read. (My eyes were getting tired really quickly when I was trying to read over my posts, but my eyesight has always been pretty shitty. I blame genetics. Let's just ignore the fact that I spend waaaaaaaay too much time on computers and waaaaaaaay too little time inside.)

This post is going to be a bit different from the other ones, in that we're focusing more on the structure of the drugs themselves and how improving the structure can improve efficacy and decrease toxic effects. Yay!

1) Demonstrate understanding of the “structure-activity relationship” and its importance during the search for better, safer drugs.

The "structure-activity relationship," as the name states, is the relationship between the structure of a drug and its activity in the body. The structure-activity relationship is all to do with drugs having to be a certain shape to fit into the receptor of interest. The better a drug fits the receptor of interest, the more likely it is to bind and have an effect. Another area of concern is that a drug might be able to fit into multiple receptors and have unwanted side-effects at the other receptors: so-called "off-target side effects." Tweaking the structure of a drug may be able to prevent this from happening.

2) Show awareness for methods used to change the structure of a drug to make it a better ligand for its target receptor.

There are several different methods used to change the structure of drugs:

• Varying the substituents so that the drug has a better "fit" with its receptor
• Adding substituents that can interact with other binding sites
• Changing the length of the "linker" (the part of the drug between the bits that actually bind to the target) so that the binding groups can bind more effectively
• Changing the size of rings- for the same reason as changing the length of the "linker"
• Rigidifying areas with moveable bonds so as to "lock in" a particular structure, and therefore also "lock in" affinity with a certain receptor

Now it's time for an example of where this knowledge has been used!

Aspirin (acetylsalicylic acid) is a very useful anti-inflammatory (Nonsteroidal Anti-Inflammatory Drug for long, NSAID for short). However, it can also cause gastric issues, especially if used long-term. It was later discovered (by a Prof John Vane, who won a Nobel Prize for his work) that aspirin has an inhibitory effect on the production of prostaglandins, which function as signalling molecules in the body. Prostaglandins are produced by the oxidation of arachidonic acid by COX-1 (cyclo-oxygenase-1), a enzyme that is inhibited by aspirin.

Later on, it was discovered that aspirin actually induced its beneficial effects by acting on COX-2, an isoform of COX-1. (Aspirin can bind to both COX-1 and COX-2.) As the binding site for COX-2 is larger than that for COX-1, the logical solution was to add extra substituents to aspirin so that the resulting drug can fit into the COX-2 binding site, but would be too large to fit into the COX-1 binding site. Hence the "Coxibs," or COX-2 selective NSAIDs, were born. Conveniently enough, their names all end with "-coxib." The coxibs have been found to induce fewer gastric ulcers than NSAIDs that block both COX-1 and COX-2.

3) Show how structure-activity knowledge helps improve the pharmacokinetic and toxicological properties of drugs.

The structure of drugs can also affect pharmacokinetic parameters such as absorption and half-life. As I've alluded to in my post about absorption and distribution, one of the factors affecting absorption is the lipophilicity and hydrophilicity of drugs. These parameters can be manipulated by adding or removing substituents. As for half-life, this can be altered by protecting oxidation-prone groups (by adding bulky "steric shields") or by removing them altogether. Another way of extending half-life is to replace hydrogen atoms with deuterium (i.e. hydrogen with one neutron), which our bodies cannot break down as quickly.

Some substituents are notorious for toxic properties, and so knowledge of structure can also pinpoint which groups may need to be removed or replaced in order to improve a drug's toxic profile. Currently studies manipulating the structure of valproate, an anticonvulsant drug with possible hepatotoxic and teratogenic effects, are being done. So far, strong differences in teratogenicity have been found across different analogues of valproate. In the future, perhaps many more drugs will be improved just by tweaking their structure a little.