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I went to a fascinating talk last night by Professor Vern Schramm of the Albert Einstein College of Medicine on “Enzymatic Transition States and Drug Design”.

Professor Schramm’s group work on developing enzyme inhibitors to treat diseases such as t-cell leukemia, gout, cancers and antibiotic resistant bacteria by carefully examining the structure of the enzyme and designing molecules based on the 3-D structure of the enzyme and it’s transition state. Some of the compounds they have developed are effective at femtomolar concentrations!

For those who aren’t familiar with enzymes, these are protein molecules which speed up biochemical reactions in the living organisms. Some enzymes are used to help assemble molecules in organisms, while others help break large molecules down to smaller, useful molecules. It has been estimated that there are around 55,000 different enzymes in the human body, helping create all of the molecules our bodies need to function.

Enzymes’s typically work as a 3-D template, aligning  and activating molecules in such a way that they will react. For example, a protease enzyme (one that breaks up proteins) will align the protein in a configuration where the bond to be broken is exposed to chemical groups in the enzyme which activate the bond so it can be broken. Because water molecules are involved in this process it may also align water molecules in a position so that they can help the reaction take place. All of this occurs in an area of an enzyme called the active site. Some enzymes can complete >100,000 reactions a second.

About 1/3 of all FDA approved drugs are enzyme inhibitors. Enzyme inhibitors can work in several different ways, for example they can inhibit enzymes that are used by micro-organisms to grow. HIV protease inhibitors, for example, are very effective at slowing down the replication of HIV and are at the core of many successful treatments for HIV infection and AIDS.  Other enzymes are can be used to adjust the rates of reactions occurring in our own bodies, for example the drug  losec, used to treat excess stomach acid, works by inhibiting an enzyme associated with the production of stomach acid.

To inhibit an enzyme, scientists typically look for molecules that will fit into the active site of the enzyme. This stops the molecules the enzyme normally react with (substrates) from getting into the active site, thereby slowing down the reaction. However, most inhibitors do not permanently occupy the active site – they will move in, then move out of the active site, slowing down rather than stopping the enzyme from acting on the substrate.

Professor Schramm’s group designs enzyme inhibitors by carefully examining the “transition state” that occurs when enzymes are reacting the substrate molecule(s). During the reaction there is a transient point where bonds between the enzyme, substrate and related molecules are halfway between being formed and broken. The 3-D shape of this transition state provides an excellent fit with the active site – the better this fit, the longer a molecule will tend to stay in the active site.

Using these transition structures, Professor Schramm and his team have developed enzyme inhibitors ( and potential drug candidates) such as DADME-immucillin-H which can occupy an active site for days (half life of 11.5 days in mice, 21 days in humans). Such inhibition is the equivalent of the Holy Grail in drug design, as if translated into a drug it could mean drugs which could be taken once a week or even once a month.

Professor Schramm’s work has an exciting New Zealand connection – while his group works on designing these new inhibitors, researchers at GlycoSyn, part of Callaghan Innovation, are working on the actual preparation of these compounds (another fascinating and challenging field of research) so they can be tested. Several molecules developed as a result of this collaboration are already in phase II trials, with some spectacular results.

An interview with Professor Schramm can also be found on Youtube:

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