UbiquinaseJohnny has a genetic disorder which leads to

overactivity of the enzyme ubiquinase.

Previous studies have determined

1) The molecule benzamide weakly binds to the active site of ubiquinase

2) The x-ray crystal stucture of ubiquinase with benzamide.

benzamide

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Shape and type complementarity polar-polar

hydrophobic-hydrophobicopposite charges

If we know the structure can score various drug candidates by how well they fit and match

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score

1. Water.to bind drug, water is displaced. Desolvation penaltysome water remains. Hard to predict and score

2. Conformational change.The target protein and the drug candidate can both be flexible.

3. Assumes the binding score can be described by a single structure. Ignores thermal motion and entropy.

Methods are useful but approximate

Fast, Rigid, Exhaustive Docking (FRED)

Fred is the program we are going to use

1. Read in a target protein structure

2. Read in a ligand with a known bound structure to define the binding site.

3. Read in the structure of a potential drug and dock and score.

4. This generates a series of structures (poses) and scores.

Using FRED

Each group has their own 100 molecule databaseGo to /Users/localadmin/DockThese 100 molecules have been previously docked and

scored.Look in

/Users/localadmin/Dock/Scores/molbase0N_score.txt(where N is your group number, 1-8)

The best scored compound is given first, note the id (ZINC followed by an 8 digit number)

Now ready to use FRED

Open Applications OpenEye Fred_receptor

Once that is up, then File Load and Load /User/local/Dock/ubiquinase.pdb

Macro 1629 heavy click on pro

Molecule molecule click on lig

Then click on Box, Tweak, Shape (for this step find the medium button and click create, this will take a little bit), Constraint

Now can dock

Trial Docking

find molecule from file, open /Users/localadmin/Dock/molbases/molbases0N.mol2 (N is your group number)

Then select your best ligand by clicking until you find your best ligand

Each group should have a different optimal ligand.

What do they have in common?

Which one has the best score?

What different structures might work better?

Do we have a drug that can cure Johnny?