DrgDscvry: Drug Discovery Science

Quick Review of Human Biology

Here are Brooke and Charlie. When we see them, we think of them as people - one whole unit.

However if you cut them open (sorry Charlie), you would find each is made of parts, called organs.

Each organ, though, is made up of millions of specialized cells.

For example, here is a healthy liver. It is important for removing toxins from your body.

However, it is really made of lots of cells. These cell are arranged in such a way that, together, they function as one organ.

Each cell, although it is really small, is very complex and is made of many different parts

Fundamental to all cells is the reliance on proteins for survival. These proteins are like tiny machines inside of the cell, each with a very specific task.

A drug works by targeting one (or more) of these proteins.

By binding to a protein, a drug can alter the function of the protein...

which then changes the way the cell acts...

causing the organ to behave differently...

and, finally, curing a disease and changing the way you feel as a person.

HIV Protease

As an example, let check out a protein that helps an HIV virus infect a cell.

HIV protease works by chopping big proteins into smaller proteins. These smaller proteins then are used to make new viruses

The large protein is fed through the hole in the protein, like a thread through a needle.

If you can find a drug that fits inside of the hole, you can block proteins from being fed through.

This would prevent the small proteins from being released, and thus would keep the virus from replicating.

This is Tipranavir, a drug that plugs that hole and is used to treat HIV infections.

But this drawing is not how the drug actually looks in the cell. Instead of being 2 dimensional, the drug assumes a 3D shape like this.

Looking at Tipranavir with HIV protease demonstrates how the drug binds.

The volume of Tipranavir fits well into the hole of the protein. This allows it to block the entrance of proteins into HIV protease.

Volume is important to binding. If a drug and a protein are trying to occupy the same point in space, they will clash. This clash disrupts binding, and decreases the effect of the drug.

However, there is more to it than just fitting into the hole (binding site).

The drug will also make specific interactions with the proteins.

These interactions come in a few varieties, and include:

Hydrogen Bonds Between -OH and =O, -NH and =O, or -NH and -OH

Electrostatic Interactions Between positive and negative charges

Greasy Interactions Between non-polar areas on both the protein and drug

Cation-Pi Interactions Between a positive charge and an aromatic ring.

To see this, lets look at the Tipranavir binding site again, but zoom in to have a closer look.

Now, we add in some of the protein’s atoms as well.

We can then draw in some of the hydrogen bonds being made by this drug.

Lets also check out some of the greasy interactions between the drug and the protein.

Here is a part of the hole in HIV protease, we will call a pocket.

It is made mainly of non-polar atoms.

A drug that could fit non-polar atoms in this pocket would improve its binding by increasing greasy interactions

Here is Tipranavir, with its volume outlined with a mesh. Greasy atoms here fit well into this pocket.

Additionally, the positive charge on the protein here can make a cation-pi interaction with the aromatic ring on the drug.

So, as is the case in Tipranavir binding to HIV protease, drugs bind to proteins when:

1) The drug’s volume compliments pockets in the protein at the binding site.

2) The drug has chemical groups that can be aligned in the binding site to form good interactions with the protein atoms.

Disclaimer - this is a simplification of the actual situation, but serves our purposes sufficiently.

Drug Discovery

Given the information in the two previous sections, we propose the following statement:

Molecules that have a similar shape and arrangement of chemical groups to a drug could bind to a protein in a similar way, and thus have a similar effect when treating a disease.

If this is true, then we don’t even need to know what the protein looks like in order to come up with new potential drugs.

This is a good thing, because determining the structure of a protein is a difficult thing.

Lets see how this is done.

We first take a molecule we know to have a desired effect, like a drug, and we create a a 3D representation of it.

Using a computer, we can calculate the volume of the drug.

We also make 3D representations, and calculate the volumes for, of a bunch of test molecules. Here is one, where the volume is shown in blue mesh.

You then overlay the two structures, trying to match the shapes of the molecules as much as possible. Here, we have overlaid Tipranavir with the compound shown in the previously.