From Targets to drugs -III

All hits do not convert into a drug molecule.

Suppose one finds a small organic molecule that seems to inhibit the activity of the protein of interest, what does it really mean? It means nothing because we have to prove that it is effective in vitro as well as in vivo.

The first thing that any chemist or biologist will ask is what is the binding constant. Binding constants are nothing but the concentration of the inhibitor that is required to bind to the protein and inhibits its activity by say 50% (This is a gross exaggeration but this is the simplest I can explain Michealis-Menten equation.). The lower this number the better the inhibitor. Typically, we look for molecule that will have a binding constant in the order of sub micromolar or nanomolar range. That is a tall order. Not all molecules that we discover will bind in that range.

There are other consideration. The molecule or drug should be such that it can enter into the cell easily. This is again a tall order because each cell has a bilayer membrane made of lipid molecules. So essentially you are looking at non-polar molecules or molecules whose charges are not exposed.

The molecule should be small in size so that it can diffuse into the cell. If it is large molecule then it will require special channels or pores to enter into the cell.

The molecule should be specific to the protein of your interest. In other words, look at the protein I work with. As I said it hydrolyzes ATP. Now, there are thousands of proteins inside the cell that can breakdown ATP. If I want to create a drug that inhibits the ATP activity of my protein, I need to make it absolutely specific so that only my protein is inhibited. This becomes absolutely important when you consider that a drug has no specificity with regards to the cell it enters. It can be a diseased cell or a normal cell. What you look for when you create drug molecules is that in the diseased cell, the protein of your interest is present and if you target it then the diseased cell will be killed. However, you cannot prevent your drug molecule from entering into normal cell and therefore, if you have a non-specific drug it will kill the normal cell too, creating havoc.

So you see getting a drug molecule is a tall order. It is has to be small molecule, specific to one protein, and binding to it very tightly.

If you succeed in finding such a molecule, then comes the next part. You have to show that it is not toxic. So each drug has to pass through pharmocokinetics studies. You have to show that the drug molecule is not creating unwanted side effects, it is not carcinogenic and it is not going to alter the DNA make up your cell. You have to also show how it is metabolized and excreated from the system. These studies are done in animals.

Once it has passed this stage, the human trials begin. Only then the FDA gives approval for a drug to be marketed.

These studies take time. The average success rate is between 1-2% and it can take up to 20-30 years of intense studies to market a drug.

Can this time be cut down? Yes, if we know how to make proteins in large quantities and solve their structure. If we have better programming tools for in silico studies. In fact, many pharmaceuticals are also looking at alternative models for pharmocokinetics studies. If we are successful in eliminating or reducing even one of the bottlenecks, we can drastically cut down the time.