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Heart disease chemistry 1

Watch David discuss the biochemistry of cholesterol formation, the discovery and design of the statin drugs and the interactions they make.
DAVID MANALLACK: Hi. Among the biggest selling drugs today are the statins, and their discovery has been heralded as the most significant in the pharmaceutical industry in the last few decades. Statins are a group of agents that lower blood cholesterol levels and they’ve had a huge impact on reducing cardiovascular disease worldwide. In this module, we will consider the biosynthesis of cholesterol and the mechanism of action of the statins. In development terms, two broad classes of compounds have emerged with origins that can all be traced back to natural substances. And it’s a fascinating story, combining the clever applications of both chemistry and biochemistry to produce these, our statin drugs, that have had such a huge impact on modern medicine.
So let’s begin with cholesterol. Cholesterol is a complex hydrophobic molecule that’s vital for normal cell function. The structure, shown here, is a molecule with a four ring system with many substituents attached. The four ring system is known as a steroid scaffold and is associated with numerous biochemical pathways. The groups attached to the steroid are mostly hydrophobic.
Not only do we get cholesterol through our diet, but we also make it in our cells. And the mere mention of the word cholesterol conjures up greasy meals. And for some time we’ve been aware of the link between high levels of cholesterol in the blood and cardiovascular disease. Looking at this from a rational point of view suggests that reducing plasma cholesterol levels would be a convenient way of reducing atherosclerosis and coronary heart disease. And indeed, this simple approach works and is now adopted as a strategy to combat heart disease.
The simplest way of reducing cholesterol is to cut out certain foods, but for some people such as Steve Park and myself, this is not enough to reduce cholesterol to safe levels. This means that we need to tackle the cellular production of cholesterol. And to do that we need to understand how it is made. Over 30 enzymes are involved in the production of cholesterol within our cells. So which step did the early researchers choose to block? And the answer was to look for an enzyme that catalysed a vital step in the production of cholesterol. This step is shown here and it involves the production of mevalonic acid or R-mevalonate, an important building block in the generation of cholesterol.
Reducing the production of mevalonic acid has the knock on effect of greatly reducing the cellular generation of cholesterol. In this diagram, we commence with the molecule HMG-CoA, which we will call the substrate of the enzyme. On the left hand side we have CoA, which is attached to a sulphur atom. And CoA is a complex molecular fragment that we will simply refer to as CoA in the future. Adjacent to the sulphur atom is a carbonyl group. It’s a carbon with a double bond to an oxygen. This is then connected to a short chain with a hydroxyl group attached. And the last part of HMG-CoA is a carboxylic acid group.
The enzyme involved in this molecular transformation is known as HMG-CoA reductase, and its role is to remove and modify the left hand side so HMG-CoA.
As we can see in our product of this reaction, the chain now terminates with a hydroxyl group.
Armed with this biochemical knowledge, drug discovery research teams then commenced the search for drugs that blocked HMG-CoA reductase, our enzyme. And by blocking the enzyme we block cholesterol production. We now travel back to the 20th century, where in the 1970s three labs based in Tokyo, Rahway, New Jersey, and in England simultaneously discovered the statins.
But where did they start and what strategy did they follow? The search for the enzyme inhibitors of HMG-CoA reductase began by following the same logic used for finding antibiotics. As microorganisms are constantly battling each other for resources and space, they have developed chemical weapons against each other. The researchers considered that an organism which didn’t require HMG-CoA reductase for survival purposes might, in fact, produce inhibitors of this enzyme. And so it was. Extracts of various fungal organisms produced substances that were extremely potent inhibitors of the enzyme. The first of these compounds was found during the screening of at least 6,000 microbes and was named mevastatin. Let’s have a look at it now.
As with many natural products, mevastatin is a complex molecule that is difficult to synthesise in the lab. The compound has interesting features including what we’re going to call a polar head group that we will return to later. The polar head group comprises a six membered ring with an oxygen atom. The ring also has a carbonyl group and a hydroxyl group. It is attached through a short chain to a hydrophobic section that comprises two six membered rings fused together. A further chain through an ester group completes the molecule on the left hand side. The drug mevastatin was unfortunately never successful, but it paved the way to other compounds.
Two important molecules that emerged were lovastatin and simvastatin. Like mevastatin, lovastatin is also a natural product. However, simvastatin is what we would call semi-synthetic, whereby a natural product is used as the starting point for an organic chemistry manipulation. In this case, we’ve added a methyl group. Now, I said we’d return to the polar head group. In each of the compounds shown so far, our polar head group is shown as a six-membered ring with an oxygen atom. This, however, is not the active form of the drug. First of all, I’m going to rotate the structure. Our polar head group is now shown on the right hand side. In the body, enzymes convert the ring to an open form.
First of all, we’ve highlighted the polar head group. Ring open form is the active drug shown here on the right. In other words, the molecule on the left hand side is a pro drug. By itself, the pro drug is inactive and only blocks cholesterol formation once it has been converted to the ring opened form on the right. If you look closely at the right hand side of the converted compound there are similarities to something we’ve seen before. Now let me show you.
The right hand side consists of a hydroxyl group placed near a carboxylic acid. This is reminiscent of both HMG-CoA and mevalonate, where we see both a hydroxyl group and a carboxylic acid. So in other words, when the statin is opened up it is able to mimic both the substrate and product or our HMG-CoA enzyme. Interestingly, this small section of the drug highlighted in red is insufficient to stop the enzyme from working, but it gives the spatial and chemical match needed to fit within the enzyme. The high potency of the statins is provided by the lipophilic 6, 6 ring system that’s fused together.
The complexity of these early molecules was a prompt for more research to develop compounds with improved properties that were easier to manufacture.
The following article will take you through the next generation of statin drugs and show you how they interact with the enzyme HMG-CoA reductase.

Watch David discuss the biochemistry of cholesterol formation, the discovery and design of the statin drugs and the interactions they make with the enzyme.

As you make your way through the course, you may like to return to this video and replay particular sections to review David’s presentation on heart disease chemistry.

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The Science of Medicines

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