From Targets to Drugs-Part I

It takes anywhere from 20 to 30 years of intense research to get a drug to the market.

This is a long discourse on biological principles and I will try to make it as simple as possible.

There are two types of cells on this planet: bacterial and eukaryotic. The eukaryotic cells encompass protozoan cells, mammalian cells, yeast cells, and plant cells.

Though there are lots of differences between the various kinds of cells, most of the biological processes are common. For example, the way glucose is utilized inside a cell to generate energy is more or less uniform across the vast span of different cells. What biologists try to do is to exploit subtle differences between various organisms. A case point is an enzyme called thymidine kinase. It is made both by human cells and herpes virus cells. The enzyme performs the same catalytic reaction. However, there is a difference in the structure of the two enzymes and this could be neatly exploited to generate drugs that will inhibit only Herpes virus Thymidine kinase but not the mammalian cells.

This is the Holy Grail that biologists search for in their life times while trying to discover drugs. Small subtle differences that can be used as drug target.

Identification of drug target involves understanding the biology of an organism. It means that we have to study the proteins that are involved in doing the biochemical reaction. This is the first bottleneck.

To understand a reaction, where do we start? With the advent of Genome sequencing, we know the sequences of many organisms. But all we really know is the way ATGC is organized. We do not know what it means. We do not know which of these particular organization of ATGC encodes for a protein. That is where computational biology comes into picture. We use computer programs to predict the coding sequences. Even if we assume we can accurately predict the protein encoding genes, we do not know what the protein does. Even for something that has been well studied like E.coli, there is a substantial genome data that we do not understand. For human sequences, we do not know the function of more than 80% of the proteins. For pathogenic organisms we know even less.

Therefore, our first goal becomes to understand the biology of an organism, to find our favourite protein and to study it.

Let me put this in a little bit perspective. The protein I work with was initially purified from calf thymus tissues. I would take 10 kg of calf thymus tissues and process it through various stages to get less than a microgram of pure protein. This amount is useless for anything but basic reactions.

What researchers do is to take the DNA encoding the protein into E.coli and ask the bacteria to produce it. As E.coli is easier to grow, theoretically we should be able to produce humongous amount. Ah! this is the second bottleneck.

As my E.coli cells are thawing and I have to start a protein preparation, I am going to stop here and continue with this exposition tomorrow.