Rational Drug Design

Question 1

What is required for computational docking?

Answer 1

A good resolution structure

Question 2

Outline how computational docking works

Answer 2

• Use computer to generate very large numbers of configuration of ligand/receptor
• Asses their energies using a force field

Question 3

What does the force field in computational docking compute?

Answer 3

The binding energy, the ΔG from the structure and all interactions

Question 4

What order is computational docking done in?

Answer 4

• Current drugs known to be tolerated
• Known chemicals with drug-like properties
• Entirely model molecules which might fit

Question 5

What is the issue with model molecules being used as part of rational drug design?

Answer 5

They must be synthesised before they can be tested

Question 6

What is the function of M^{<span>pro </span>}in coronavirus?

Answer 6

It releases functional proteins from large polyproteins

Question 7

What is the target for M^pro?

Answer 7

Linker sequences

Question 8

What general structure occurs in coronavirus linker sequences?

Answer 8

Glutamine followed by an amino acid with a small side chain

Question 9

How can the coronavirus M^pro active site binding to the substrate be visualised?

Answer 9

By replacing one of main catalytic amino acids e.g C145A

Question 10

How was the N3 inhibitor for coronavirus produced?

Answer 10

Peptide sequence corresponding to linker sequence where glutamine replaced by similar chemical and altered so when ‘peptide’ bond attacked it forms a covalent bond

Question 11

Why do peptides make poor drugs?

Answer 11

• Can be hydolysed by proteases in blood
• Poor pharmacokinetics

Question 12

What characteristics do useful drugs usually have?

Answer 12

• Small
• More hydrophobic

Question 13

What assay was used to assess the efficacy of the N3 inhibitor for coronavirus?

Answer 13

• MCA molecule on N terminus and DNP molecule on C terminus
• When cleaved DNP can no longer quench the fluorescence of MCA