Theme 5 Lecture 19

Question 1

Schering-Plough cannabinoid receptor antagonists.CBR1 ligand (Rimonabant)

Answer 1

They were anti-obesity drugs
Was effective but withdrawn from the market
Caused depression and suicidal thoughts.

Question 2

Pharmacophore model built from eight existing antagonist and inverse agonist CB1R ligands.

Answer 2

3d model of each structure was made.
Identified key pharmacophoric elements like HBA,AR and HPO.
The catalyst was used to generate these features.

Question 3

What was the selected model used?

Answer 3

The one that fitted rimonabant the best.
(superimposed)

Question 4

Screening process

Answer 4

Compound library screened 500k
22k hits
Filtered via MW,LogP,HBA,HBD and rotatable bonds
7k left filtered by probability of activty.
2k in to similar groups
top compound from each group tested for the effect against the cannabinoid receptor
5 compounds inhibited 50% inhibition

Question 5

Give me the definitions of agonist, antagonist and inverse antagonist

Answer 5

Ligand that binds to a receptor and alters the receptor state causing a biological action
Binds to a ligand and reduces the effect of the agonist, they have affinity but no efficacy.
A ligand which binds to receptor site and causes a change in the receptors state reducing a biological response,

Question 6

Define the term rotatable bonds:

Answer 6

Rotatable bonds are any single bond not around a heavy non-terminal bond.
Veber excluded C-N amide due to high partial bond character, therefore a rotational energy barrier.

Question 7

Referring to Gibb’s Free Energy (ΔG) explain how reducing nRot might be beneficial when considering ligand-target interaction.

Answer 7

Rotatable bonds exert a entropic penalty.

So, fewer wiggly parts in the key (reducing nRot) can lead to a better fit in the lock (the ligand-target interaction), and that’s generally what you want for a drug to work well.
Thus being a more positive ΔG making the reaction more favourable.

Question 8

What is the role of PDE enzymes in phosphoester hydrolysis and how do metal ions contribute to this process?

Answer 8

PDEs break down cyclic nucleotides like cAMP which is crucial for cell signalling.

Zinc acts as a lewis acid which makes the molecule more reactive to water.

Water then attacks and breaks the bond releasing an alkoxy group which takes a proton from His613

Question 9

PDE10A to treat schizophrenia (triaryl imidazole)

Answer 9

PDE10A is found in the striatum of the brain and would be expected to increase cgMP levels in this specific location.

Compound library was screened in an assay and triaryl imidazole 10 was found.

Question 10

Interactions showing good activity and high affinity

Answer 10

GLN-276- aromatic ring

Thiophene occupies selectivity pocket.

Gly-725 is replaced by a larger amino acid blocking access to the selectivity pocket

Tyr-693 is ideally positioned to form a H-bond.

Question 11

What are the therapeutic uses of PDE3, PDE4, and PDE5 inhibitors?

Answer 11

Cilostazol (PDE3 inhibitor) is used for intermittent claudication in peripheral vascular disease (PVD).
Roflumilast (PDE4 inhibitor) is used to treat chronic obstructive pulmonary disease (COPD).
Sildenafil (PDE5 inhibitor) treats erectile dysfunction.

Question 12

Second round of screening performed.

Answer 12

Potential to fit the selectivity pocket and form a H-bond with Tyr-693.
And to obey the physical parameters such as BBB, PERMEABILITY,Mw, moderate lipophilicity and minimal H-bond donors)

Question 13

What is LE

Answer 13

LE is ligand efficiency which is a metric unit used in the optimization process= gives you the average binding per atom.

Question 14

What happened with the in-vivo study?

Answer 14

Showed poor brain permeability and the concentration was 36 times higher.

Question 15

SAR specific groups

Answer 15

The 4-pyridine moiety is optimal. Removal of the N or movement around the ring gives less active compounds.
Methylation of the pyrazole NH moiety improves brain penetration and is optimal. IMPROVES BBB PERMEABILITY

The quinoline system is optimal, with other bicyclic heterocycles being less active.

Question 16

Exercise 2 look at slide 16

Answer 16

The above rationale says its bonded via a amino-pi interaction, this is false because it is bonded via an amide.

The correct terms would be its bonded via an amide with H-bonding

BBB is affected by Mw, lipophilicity and H bond donors

Smaller molecules move easier in the brain, lipophilic molecules are more fat loving, HBA cause a hydrophilic environment-too many are not good for the BBB.

LLE: Also known as lipophilic efficiency (LiPE). Links potency and lipophilicity, and provides an aggregate indicator of druglikeness.

LE: Effectively binding energy per atom of ligand.