Theme 5 Lecture 16 Optimization of drug targets

Question 1

Lead optimisation (theme 3)

Answer 1

target selection-hit identification-lead identification- lead optimisation- candidate drug nomination -pre clinical development

Question 2

LO process and identification of clinical candidates

Answer 2

Iterative process
In vitro assays then secondary as well as in vivo animal models.
Aims to identify clinical candidates with optimal potency, selectivity, efficacy, physical and pharmaceutical properties, and safety profile​​.

Question 3

This process covers 3 main activities, what are they?

Answer 3

1)Optimisation of drug-target interactions via testing the bio activity of compounds in the assays(prim and sec)
2)Of drug like properties
3)In vivo testing for toxicity and safety= pre clinical studies (PHARMACEUTICAL TYPE PROPERTIES)

Question 4

Importance of binding

Answer 4

In order for biological activity, the ligand needs to bind to its target.
High affinity and potency for the drugs=lower conc
High affinity for on target sites/low for off target=lower side effect

Understanding specific ligand- target interaction is essential for affinity

Question 5

Binding as an equilibrium process, what is the equation?

Answer 5

Kd=(B)(P)/(BP)
The top is unbound and bottom is bound
Smaller Kd= higher affinity
The direction of the equation is solely relied on the Kd( moves right=unbound and left etc)

Question 6

Energetics Of binding

Answer 6

Binding can only occur if it is energetically favourable
Enthalpy and entropy
Enthalpy is what you want for the reaction to be favourable which is deltaH, deltaS is entropy
Enthalpy which is deltaH needs to be more negative in order to be favourable.

Question 7

∆𝐆 =∆𝐇−𝐓∆𝐒
Enthalpic consideration

Answer 7

Formation of the binding interactions between D and P=favourable interactions between h-bonding, dipoles(placements of F groups) and weaker VdW(good size and shape complementary)

Ligand(D) desolvation= increased water-water H-bonding enthalpic gains
Binding pocket (P)= Water-water interactions h bonding=enthalpic gains

Question 8

Entropic considerations

Answer 8

Reduced rotational and translational freedom in DP compared to D+P
Water is in disordered state for desolvation and binding pocket
When its in the disordered state it can make more interactions with itself rather than interacting with the ligand

Question 9

How does the equilibrium dissociation constant of a drug-target interaction relate to the Gibbs free energy of binding

Answer 9

∆𝑮 = −𝑹𝑻 𝒍𝒏 𝑲𝒅
∆𝑮= GIBBS FREE ENERGY OF BINDING
R=gas constant
T=temperature

Question 10

Typical non-covalent drug target intercations

Answer 10

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 electron density)

𝜋-𝜋: Orbital interaction between two 𝜋-systems

VdW: hydrophobic interactions

Question 11

What do hydrophobic aliphatic interactions cause?

Answer 11

These cause desolvation at the binding site so can be entropically or enthalpic favourable

Question 12

Some drugs bind through a covalent mechanism

Answer 12

Strongest type of interaction
Attack on the electrophilic centre by a nucleophilic protein residue.

Question 13

Drug binding can compromise interactions (shape of drug)

Answer 13

The better the shape and fit of the drug in the binding pocket with good placement of the functional groups leads to higher affinity of the drugs.

This due to more favourable reactions with the proteins.

Question 14

Drug stereochemistry is important, look at the photo on slide 14.

Answer 14

3 point contact model
R and S enantiomer
R has the 3 point contact with Pi-Pi, ionic and H bond-=more optimal
Whereas S has Pi-Pi and ionic but lacks H-bond.

Question 15

3 types of enantiomers

Answer 15

eutomer- active
distomer- less
Eudismic- ratio of both=more stereoselectivity

Question 16

Absorption, metabolism, excretion and toxicity

Answer 16

Different enantiomers don’t differ in their physical properties.
A= S-mtX undergoes absorptions after oral
M= L-Methadone is metabolised faster than D-meth
E= related to formation of the metabolites
T= Differences in interactions with the protein

Question 17

Why is the pioglitazone enantiomer not synthesised as a single enantiomer

Answer 17

Both enantiomers exhibit similar properties thus would be more cost effective to synthesise 1 as a racemate rather than a single enantiomer.

Question 18

recognising R and S enantiomers

Answer 18

Find chiral centre, then assign numbers next to the atoms according to atomic number.
R is clockwise and S in anticlockwise
But if group 4 is in front on the plane, it will be S.

Question 19

Vinylogous acid

Answer 19

Double bonded oxygen through pyridine rings to a OH.
Double bonded oxygen usually bonds through dipole-dipole, ion dipole or a HBA.
OH usually HBA or HBD or ionion
In this case Oxygen is deprotonated and has a charge and through conjugation the charge moves across to the other oxygen.