3D drug design

Exercise 1:

In mutation studies, all individual amino acid residues are mutated, usually to alanine. The researchers look at the effect on the function of the protein: Does the mutated protein work better, worse, or not at all? Most mutations have little or no effect. The mutation of important residues will have a significant effect: usually, a protein will lose its function completely when an important amino acid is mutated.

Exercise 3:

1. The standard atoms in proteins are carbon, nitrogen, oxygen, sulfur and hydrogen.
2. Atoms in Yasara are coloured as follows:
   • Red: oxygen
   • Dark blue: nitrogen
   • Green: sulfur
   • Light blue: carbon

Exercise 4:

• White bonds: single (covalent) bonds
• Yellow bonds: double (covalent) bonds

Exercise 5:

1. The three types of interactions are:
   • Green: hydrogen bonds
   • Blue: ionic interactions / salt bridges
   • Orange: hydrophobic interactions
2. Look at the drawing of interactions

Exercise 7:

• Blue parts: α-helix
• Red parts: β-strand (many strands together form a β-sheet)

Exercise 8:

• Double bonded oxygen: Ball and stick
• Peptide bond: (Ball and) stick
• Histidine: Any representation showing side chains
• Alfa helix: Backbone-trace or cartoon
• Disulfide bond: Stick

The answers depend on your own preference. Only representations where you really don't see the object are wrong. The purpose of this exercise it to show you that although the ball-representation is the most realistic, it is not always the most practical.

Exercise 9:

A cavity has a relatively large contact surface which allows for many interactions (H-bonds, ionic interactions, hydrophobic interactions). This will increase the specificity of the active site for a particular ligand, compared to an active site not located in a cavity.

Exercise 11:

The best known example is hemoglobin. Other possibilities are calmodulin, thrombokinase, cytochromes and many others.

Exercise 14:

The lock-and-key principle states that the enzyme (the lock) will only work if the right ligand (key) is used. One of the assumptions of this principle is that the enzyme's shape barely changes.

Exercise 16:

View the marked atoms below. Most of them can form hydrogen bonds. The -SH group (thiol-group) can only form very weak hydrogen bonds, although in theory it could form one. The negatively charged oxygen in candidate 2 (C) can form an ionic bond with the ligand. Note: the charge is distributed of the whole carboxyl group. The ionic bond is therefore formed by the whole group (the charged oxygen and the doubly bounded oxygen).

Final question:

Adapted ligand 2 (ligand C) is the best candidate to be used as antidote. In this ligand, the peptide bond forms two hydrogen bonds and the carboxyl group makes a very strong salt bridge with the zinc ion of the protein. The other ligands have fewer (or less strong) interactions and will not bind as well.

You can watch the ligand with the interactions drawn as sticks in Yasara. Load them via File > Load > Complete scene > int1.sce, int2.sce and int3.sce.