Quick Review of Human Biology

Quick Review of Human Biology

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

whole unit.

Quick Review of Human Biology

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

whole unit.

Maybe one and a half people?

Quick Review of Human Biology

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

whole unit.

Maybe one and a half people?

(the other half is high priest vatican warlock)

Quick Review of Human Biology

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

parts, called organs.

Quick Review of Human Biology

lungs

heart

eye

brain

intestines

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

parts, called organs.

Well, organs and tiger’s blood, in the case of Mr. Sheen.

Quick Review of Human Biology

lungs

heart

eye

brain

intestines

Quick Review of Human Biology

Quick Review of Human BiologyEach organ, though, is made up of millions of specialized cells.

Quick Review of Human BiologyEach 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.

Quick Review of Human BiologyEach 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.

(Charlie’s mortal enemy)

Quick Review of Human BiologyEach 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.

(Charlie’s mortal enemy)

Quick Review of Human Biology

Quick Review of Human BiologyEach cell, although it is really small, is very complex and is

made of many different parts

Quick Review of Human BiologyEach 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.

Quick Review of Human Biology

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

Quick Review of Human Biology

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

Quick Review of Human Biology

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

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

Quick Review of Human Biology

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

which then changes the way the cell acts...

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

Quick Review of Human Biology

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...

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

Quick Review of Human Biology

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

HIV Protease

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

HIV Protease

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

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

viruses

HIV Protease

HIV Protease

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

HIV Protease

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

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

HIV Protease

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

If you can find a drug that fits inside of this 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

HIV Protease

HIV ProteaseThis is Tipranavir, a drug that plugs that hole and is used to

treat HIV infections.

HIV ProteaseThis 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.

Oxygen = Red. Nitrogen = Dark Blue. Sulfur = Yellow. Fluorine = Light Blue. Carbon = Pink

HIV Protease

HIV ProteaseLooking at Tipranavir with HIV protease demonstrates how

the drug binds.

HIV ProteaseLooking at Tipranavir with HIV protease demonstrates how

the drug binds.

Volume of TipranavirTipranavir

HIV ProteaseLooking at Tipranavir with HIV protease demonstrates how

the drug binds.

Volume of TipranavirTipranavir

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

protease.

HIV Protease

HIV ProteaseVolume 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.

HIV ProteaseVolume 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).

HIV ProteaseVolume 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.

HIV ProteaseVolume 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 BondsBetween -OH and =O, -NH and =O, or -NH and -OH

Electrostatic InteractionsBetween positive and negative charges

Greasy InetractionsBetween non-polar areas on both the protein and drug

Cation-Pi InteractionsBetween a positive charge and an aromatic ring

HIV Protease

HIV ProteaseTo see this, lets look at the Tipranavir binding site again, but

zoom in to have a closer look.

HIV ProteaseTo see this, lets look at the Tipranavir binding site again, but

zoom in to have a closer look.

HIV ProteaseTo see this, lets look at the Tipranavir binding site again, but

zoom in to have a closer look.

Volume of TipranavirTipranavir

HIV Protease

HIV Protease

HIV Protease

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

HIV Protease

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

Protein atoms

HIV Protease

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

Protein atoms

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

HIV Protease

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

HIV Protease

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

HIV Protease

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

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

HIV Protease

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

It is made mainly of non-polar atoms.

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

HIV Protease

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

HIV Protease

HIV ProteaseHere is Tipranavir, with its volume outlined with a mesh.

HIV ProteaseHere is Tipranavir, with its volume outlined with a mesh.

Greasy atoms here fit well into this pocket

HIV ProteaseHere 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.

HIV ProteaseHere 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.

HIV Protease

HIV Protease

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

HIV Protease

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.

HIV Protease

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.

HIV Protease

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

Drug DiscoveryGiven 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.

Drug DiscoveryGiven 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.

Drug DiscoveryGiven 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.

Drug DiscoveryGiven 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.

My magical fingertips can’t even simplify crystallography!

Drug Discovery

Lets see how this is done.

Drug Discovery

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.

Drug Discovery

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.

Drug Discovery

Drug Discovery

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

Drug Discovery

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

Drug Discovery

Drug Discovery

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 previous slide.

Drug Discovery

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 previous slide.

Drug Discovery

Although they don’t match perfectly, the shapes are fairly similar.

Drug Discovery

Drug DiscoveryYou can also look at the structures of the two molecules to

identify places where they have similar chemical groups

Drug DiscoveryYou can also look at the structures of the two molecules to

identify places where they have similar chemical groups

For example, the two molecules both have greasy, non-polar groups here and here (black dotted circles).

Drug DiscoveryYou can also look at the structures of the two molecules to

identify places where they have similar chemical groups

For example, the two molecules both have greasy, non-polar groups here and here (black dotted circles).

Also, the two molecules share hydrogen bonding groups in the places circled in green.

So, you might guess this new molecule can bind in the same way to the same protein (HIV Protease)...

Drug Discovery

Drug Discovery

...and you would be right.

Drug Discovery

...and you would be right.

Here is the molecule we matched to Tipranavir bound to HIV protease

Drug Discovery

...and you would be right.

Here is the molecule we matched to Tipranavir bound to HIV protease

The process just decribed is called Ligand-Based Drug Discovery. Now, its your turn.

Playing The Game

Playing The Game

You will be given one molecule (a query) which is known to bind to a particular protein of interest.

Playing The Game

You will be given one molecule (a query) which is known to bind to a particular protein of interest.

In addition, you will get a list of 100 molecules to compare to the query. 10 of these are also able to bind the protein, while 90

are not.

Playing The Game

You will be given one molecule (a query) which is known to bind to a particular protein of interest.

In addition, you will get a list of 100 molecules to compare to the query. 10 of these are also able to bind the protein, while 90

are not.

Compare the overlays of the 100 molecules to the query, and try to pick the ones you think are able to bind.

Playing The Game

You will be given one molecule (a query) which is known to bind to a particular protein of interest.

In addition, you will get a list of 100 molecules to compare to the query. 10 of these are also able to bind the protein, while 90

are not.

Compare the overlays of the 100 molecules to the query, and try to pick the ones you think are able to bind.

In addition, you can use the ‘bulls-eye’ to set retraints on certain atoms in both molecules. This is useful to try and match a

certain chemical group, for example.

Playing The Game

could do some more, if you guys give me some

screenshots. or, feel free to write the rest of this portion.