Theme 5-Drug Target Interactions and the Pharmacophore Flashcards
Indicate the 3 main activities in Lead optimisation process
- Optimisation of drug-target interactions
- Optimisation Druglike properties
- In vivo testing for toxicity/safety leading to preclinical studies and drug
development
Why is the optimal target binding of a ligand with its biological target is critical?
Because:
1. optimal target binding of a ligand with its biological target.
2. High affinity and potency allow lower dosing
3. High on-target affinity/low off-target affinity (selectivity) affords fewer side effects
How is affinity measured?
Affinity is measured by the equilibrium dissociation constant (Kd)
kd=([D][P]/[DP])
What is small Kd mean in realation with affinity?
Smaller Kd means higher affinity
why should be consider enthalpy (ΔH) and entropy (ΔS) for affinity optimization?
ΔH relates to the energetics of specific drug-target interactions
ΔS relates to disorder in the system and generally opposes ΔH
For affinity optimization, maximise enthalpy (favorable interactions) and minimise
entropy ( penalty when the interactions are favorable) is the goal.
What can be consider in terms on enthalpic and entropic in formation of
binding
interactions
between D and
P process?
- Enthalpic gains from favourable interactions
- Reduced rotational and translational
freedom in DP compared to D + P - Non- polar surface is reduce due to the ligand bind so increase the amount of disordered water.
What can be consider in terms on enthalpic and entropic in Ligand (D) disolvation?
Enthalpic consideration:
-Loss of favourable interactions with water (e.g. H-bonding) for polar ligands.
-Enthalpic gains from increased water-water hydrogen bonding.
Entropic consideration:
-Structured water returns to disordered bulk state.
What can be consider in terms on enthalpic and entropic binding po cket
(P) desolvation process?
Enthalpic Considaration
-Loss of favourable interactions with water (e.g. H-bonding) for polar pockets
* Enthalpic gains from increased water-water hydrogen bonding
Entropic consideration
-Structured water returns to disordered bulk state
Indicated 2 process when entropic is more favorable and 2 process for entropic penalty.
Entropic penalty
-Solvated ligand
-Ordered water
Entropic favourable
- Desolvated ligand
- Disordered water
What properties are optimised during the lead optimisation (LO) process?
Biological activity, physical properties and pharmaceutical/druglike properties
How does the equilibrium dissociation constant of a drug-target interaction relate to the Gibbs free energy of binding?
ΔG = Gibbs free energy of binding; R = Gas constant
T = Temperature;
∆𝑮 = −𝑹𝑻 𝒍𝒏 𝑲_𝒅
Indicate the target moiety, the energy and 1 example for Ion-Ion binding interation?
- Target Moiety
-Cation: Lys, Arg
-Anion: Asp, Glu - Energy
- 5-10kcal/mol (decreases in proportion to the square of inter-atom distance) - Example
(Image)
Indicate the target moiety, the energy and 1 example for hidrogen-bonding binding interation?
- Target Moiety
Backbone amides
OH - Ser, Thr, Tyr
NH - Lys, Arg, His - Energy
2-5 kcal/mol (linear geometry important with a distance of ~2.4-3.0 Å, non-classical H-bonding also possible, e.g. NH-π) - Example
(image)
Indicate the target moiety, the energy and 1 example for ion-dipole binding interation?
- Target Moiety
- Energy
0.5-2.0 Kcal/mol - Example
(image)
Indicate the target moiety, the energy and 1 example for cation-TT binding interation?
- Target Moiety
Cation: Lys, Arg
π donor: Phe, Trp, Tyr - Energy
0.2-2.5 Kcal/mol - Example
(image)
Indicate the target moiety, the energy and 1 example for TT-TT binding interation?
- Target Moiety
Phe, Tyr, Trp, His - Energy
0.5-1.0 kcal/mol - Example
(image)
Indicate the target moiety, the energy and 1 example for Van der waals binding interation?
1.Target Moiety
Ala, Val, Leu, Ile
2. Energy
0.5-1.0 kcal/mol (caused by temporary dipoles generated through perturbations in electron density)
3. Example (Image)
Note: Perturbation of electron density.
Indicate the target moiety, the energy and 1 example for dipole-dipole binding interation?
1.Target Moiety
Backbone carbonyls
2. Energy
2-5 kcal/mol
3. Example (Image)
Explain the covalent mechanism and the energy interaction.
Covalent bond are the strongest type of interaction (50-150 kcal/mol). Normally formed through attack of an electrophilic centre on the drug by a nucleophilic protein residue.
What make a strong affinity in relation with the shape and interactions?
Stronger affinity is when the better the shape and fit of the drug to its binding pocket and the more favourable interactions that can be made.
Note: The overall binding affinity of a drug is usually the result of multiple individual interactions with the protein target.
Why is drug stereochemistry important?
Drug stereochemistry is important due to one enantiomer may bind more optimally due to the
orientation of functional groups in 3D space than other enentiomer.
In addition to binding at the desired protein target, enantiomers can exhibit
differential behaviour in other processes following oral administration such as:
- Absoption
-Metabolism
- Excretion
- Toxicity
-
- Identify five types of molecular interactions that the given fragment can make with a protein target.
- Identify which atoms or moieties are involved in each type of interaction.
For each type of interaction, briefly describe in chemical terms why the interaction takes place.
- Ion-ion
Electrostatic interaction between two opposite formal charges - H-bonding
Electrostatic interaction between an electron-deficient hydrogen bonded to an electronegative atom (e.g. N, O, F) and the lone pair of electrons on an electronegative atom (e.g. N, O) - Dipole-dipole Electrostatic interaction between permanent dipoles
- Ion-dipole
Electrostatic interaction between a formal ion and a fixed dipole - Cation-𝜋
Electrostatic interaction between a cation and a delocalised 𝜋-system (i.e. an area of high electrondensity) - 𝜋-𝜋
Orbital interaction between two 𝜋-systems - VdW
Transient/induced dipole interactions.
Pioglitazone is a drug used to treat diabetes. It contains an asymmetric centre on the thiadiazinedione ring (indicated by *), yet the racemate is used clinically.
- Draw the structure for the S-enantiomer of pioglitazone
- Why the racemic mixture of pioglitazone is used rather than an enantiomerically pure form.
- Pioglitazone enantiomers racemise in vivo. There was no observable advantage to administration of the pure form of the active enantiomer over the racemic mixture.
Other reasons that a racemic mixture might be used as a drug substance include:
Both enantiomers exhibit similar activity
The distomer is benign and harmless. It is more cost-effective to make/administer the drug as a racemate than to synthesise the single enantiomer.
Explain and provived the Hammett equation.
Hammett equation quantifies
the electronic properties of functional groups as a σ constant
Explain the next table
The table shows the quantifies the electronic properties of functional groups replace in aromatic ring in meta and para position.
The negative numbers (Blue) indicates electron donating groups and positive numbers (Red) indicates electron withdrawing.
Explain the meaning of Substituent Hansch-Fujita π. How can be calculate?
-Substituent Hansch-Fujita π constant describes the lipophilic contribution
of a substituent, additive, but molecule-dependent.
- Hansch-Fujita π can be calculated with the equation in the image. Where logPx is the lipophilicity of the group to change and logPH is lipophilicity of H in the position of the deserable change group.
(Compare the x group with the H)
Explain the next table
Provide the Substituent Hansch-Fujita π constant. The positive number (Red) indicate an increase lipophilic and the negative number ( Blue) indicate a Reduce lipophilic.
List some of the properties that were incorporated in early, historical QSAR.
In the Topliss decision tree shown below, SAR exploration of the 4-Cl analogue of the parent compound is followed by several options.
a. Describe how the 4-Cl group differs from each of the 4-OMe, 4-Me and 3,4-diCl groups in terms of chemical and physicochemical properties.
Me/OMe are both electron donating in the 4-position, with OMe being the strongest OMe has little impact on lipophilicity, but Me and Cl both add lipophilicity (Cl is more lipophilic) Cl and Me are comparable in size and OMe is smaller 3,4 -diCl as expected increases the electron withdrawing effect, lipophilicity and size compared to a single Cl substitutent.
The three molecules shown below are all potent antagonists at the 5-HT6
receptor.
Design a pharmacophore for 5-HT6 antagonism that is consistent with the three
structures, and map the pharmacophore onto each compound (that is, identify
which part of each molecule represents each pharmacophoric element).
Design a molecule that will test your pharmacophore hypothesis. Explain your design and what you will conclude if testing shows your new compound to:
a. Maintain or improve activity
b. Lose activity
Molecule A exchanges the N for a carbon and tests whether the positive ionizable group proposed in the pharmacophore is necessary.
If activity is maintained or improved, then the positive ionizable group is not necessary, which suggests that lipophilicity may be important.
If a loss of activity is observed, then the positive ionizable group is important; perhaps that group participates in an ionic interaction or is a H-bond acceptor.
Design a molecule that will test your pharmacophore hypothesis. Explain your design and what you will conclude if testing shows your new compound to:
a. Maintain or improve activity
b. Lose activity
Molecule B removes the aromaticity from the molecule and tests the contribution of the aromatic groups to the pharmacophore.
If activity is maintained/improved, then the aromatic rings should not be included in the pharmacophore. The role of that ring system may be to correctly orient other function groups or to act as hydrophobic group.
If a loss of activity is observed, then the aromatic ring is important; suggesting possible 𝜋-𝜋 stacking interactions.
Note: changing from a planar to a saturated ring system will change the orientation of the other substituents, and the possibility of that change contributing to the reduction in potency must be considered.
Design a molecule that will test your pharmacophore hypothesis. Explain your design and what you will conclude if testing shows your new compound to:
a. Maintain or improve activity
b. Lose activity
Molecule C would test whether the hydrogen-bond acceptor is important by removing the oxygen atoms and replacing the sulfones with a sulfide.
If activity is maintained or improved, then the hydrogen-bond acceptor is not a necessary component of the pharmacophore.
If a loss of activity is observed, then the hydrogen-bond acceptor is important for activity, or the sulfone is important for interacting with other functional groups such as a metal, or perhaps orienting the two aromatic groups appropriately.
pharmacophore model for monoamine oxidase A inhibitors is shown, it consists of a H-bond donor (D1, blue), two hydrophobic groups (H2, H4 green) and a π-stacking interaction (R6, orange). The three compounds shown beneath adhere to this pharmacophore.
- Map the features of this pharmacophore onto each structure.
SBDD was used in the design of the antiviral drug oseltamivir, which inhibits the enzyme neuraminidase. The drug structure (yellow) and an X-ray crystal structure of the drug bound
in the active site of the enzyme are shown.
- Identify a key ionic binding interaction.
Amine to Glu119. Acid to Arg371, Arg282, Arg118.
SBDD was used in the design of the antiviral drug oseltamivir, which inhibits the enzyme neuraminidase. The drug structure (yellow) and an X-ray crystal structure of the drug bound
in the active site of the enzyme are shown.
Identify a hydrogen-bonding interaction.
Acetyl carbonyl to Arg152.
SBDD was used in the design of the antiviral drug oseltamivir, which inhibits the enzyme neuraminidase. The drug structure (yellow) and an X-ray crystal structure of the drug bound
in the active site of the enzyme are shown.
Based on the view of the active site, in what pocket is the alkyl ether?
The C6 pocket
SBDD was used in the design of the antiviral drug oseltamivir, which inhibits the enzyme neuraminidase. The drug structure (yellow) and an X-ray crystal structure of the drug bound
in the active site of the enzyme are shown.
Looking at the X-ray structure, might it be wise to change the ether from a 3-pentyl to a larger alkyl group? Why or why not?
It would not be wise to change the 3-pentyl group to a much larger alkyl group. Glu276 is creating an induced-dipole interaction with the alkyl ether. If the alkyl group gets much larger than the 3-pentyl, this interaction will not be able to occur and the glutamate will most likely repel the larger nonpolar alkyl group, causing the compound to lose a key binding interaction.
