Lecture #2: Computer Assisted Drug Design

Question 1

Can develop drug specifically for:

Answer 1

• antagonism or agonism of a receptor
• inhibition of an enzyme
• interaction with DNA/RNA

Question 2

Pharmacological activity results from

Answer 2

ligang (drug) binding to biological receptor (large protein, receptor, enzyme

Question 3

Induced fit

Answer 3

conformational changes happen to both drug and receptor upon binding

Question 4

Pharmacodynamics

Answer 4

• “What the drug does to the body…”*
• Drug-receptor interactions are very specific
• Structure of lead is similar to that of the natural receptor ligand or enzyme substrate
• “Think thermodynamics”

Question 5

PHARMACOKINETICS

Answer 5

“what the body does to the drug…”*
-rates of absorption, distribution, metabolism, excretion, reaction (ADME/Tox)
-depends on water solubility, lipid solubility, physiology…
-duration of effect
-can include liberation: release of drug from its formulation “LADME/Tox”
“Think kinetics”

Question 6

Rational drug design categories

Answer 6

Structure-based (need 3d structure)

Pharmacophore-based

Question 7

Structure-based drug design steps

Answer 7

1- discover/identify target protein
2- obtain 3D model of the target protein
3- design a molecule that will interact with the target protein

Question 8

SBDD: How to Discover/identify the target protein

Answer 8

molecular biology
proteomics

liquid chromatography
mass spectrometry
2D electrophoresis

Question 9

SBDD: Obtain 3D model of the target protein

Answer 9

2nd step

Experimental:
- X-ray crystallography
- multidimensional NMR
 - 3D electron microscopy
Computational:
- homology modelling

Question 10

X-RAY CRYSTALLOGRAPHY

Answer 10

• does not typically resolve hydrogens
• ionization states can be uncertain
• can confound similar atoms
• all these factors must be addressed by molecular modeling once the x-ray structure has been deposited to the PDB
• structure in crystal may be different from that in solution

HYDROGENS AND IONIZAtTION STATES CAN BE UNRESOLVED

Question 11

NMR (NUCLEAR MAGNETIC RESONANCE

Answer 11

• Must find the 3D structure that best matches the NMR restraints (interatomic distances, dihedral angles, etc.)
• Typically finds several solutions
• Triple resonance (1H, 13C, 15N)
• Because of low natural abundance of 13C (1.1%) and 15N (0.4%) may require producing isotopically enriched protein
• Requires very high-field spectrometer
• For structures < 30 kDa

Question 12

3D ELECTRON MICROSCOPY

Answer 12

-Modern electron microscopy + 3D image processing
-take individual projection images (i.e. 2D) by TEM (transmission electron
microscopy) and reconstruct the 3D structure
-can determine structures of large proteins and macromolecular assemblies
under near-physiological conditions (cryogenic T°, no contrast agents)
-4-10 Å resolution

Question 13

HOMOLOGY MODELLING

Answer 13

1. Obtain template: known 3D structure of protein(s) with similar sequence to that of the unknown.
2. Perform sequence alignment of the unknown to that of the template.
3. Thread a 3D structure for the unknown based on the template.
4. Refine the homology model, especially loop regions.
   accuracy? template available?

Question 14

MODEL LIGAND BY EITHER:

Answer 14

Quantum mechanics (QM): 
based on the most fundamental view of electronic structure theory. Based on the Schrödinger equation. Calculations can only be done on small molecules.

Molecular mechanics (MM): based on classical physics. Uses a well- parametrized force field to obtain structures and their energies.

Question 15

SBDD CONSIDERS:

Answer 15

• 3D structure
• conformational change upon binding
• solvation effects
• thermodynamic and statistical mechanical considerations