Theme 5 Lecture 17

Question 1

What is SAR?

Answer 1

Structure activity relationship
Pharmacophore modelling is important
Ligand based drug design-based on biological activity
Structural based drug design- structural features of the ligand bound to its target
Understanding them changes in the structure is important for the biological activity

Question 2

SAR studies congeners

Answer 2

Same core structure but varying of functional groups.
Example=changing of OH to OCH3 removes the hydrogen bonding (water loving)
Thus causing changes to the lipophilicity (increases) which is associated with non-polar interactions.
H bonding is dipole dipole which is polar thus changing this would alter the polarity.

Question 3

Historical methods of quantifying SAR.(hammett equation)meta and para

Answer 3

Meta and para which is the electronic properties of functional groups.
So fluro and nitro are always in the electron withdrawing position whether they are in meta or para

Question 4

Hansch-Fujita π constant

Answer 4

A value that describes how a functional group alters the lipophilicity of a molecule and LogP

Question 5

LogP and LogD

Answer 5

Higher LogP is more lipophilic
LogD is how a molecule reacts in different pHs=how ionisable the molecule is.

Question 6

Taft=Steric size parameters (ES)

Answer 6

Measures how the size of the groups affects the behaviour of the molecules.

Question 7

MR= molar refractivity

Answer 7

Measures molecules ability to polarise light, which can tell you how the molecules interact with others.

Question 8

Explain Verloop parameters, hansch equation and free wilson?

Answer 8

Verloop parameters: substituent length L and width in 4 directions (B1-4). Calculated by the program STERIMOL. to do with size

Hansch equation correlates a number of physicochemical parameters with biological activity
log 1/C=-aπ^2+bπ+σ+cE_s+d
C = concentration where a specific activity is observed;
a,b,c,d = regression coefficients from a training set of compounds

Free-Wilson (additivity) equation assesses additive substituent effects on overall molecule (rather than component functional groups)
BA=∑a_i X_i+μ
BA = biological activity; αi = magnitude of effect for a given substituent;
μ = average activity of parent molecule; X = 1 (substituent present) or 0 (substituent absent)

Both approaches require synthesis and pharmacological analysis of a large set of training compounds

Question 9

Topliss Decision Tree, its purpose, hansch equation, advantage of free wilson/hansch?

Answer 9

Purpose: Aids in making rational decisions about which chemical analogues (variations) of a drug to synthesize next in Structure-Activity Relationship (SAR) studies.

Starting Point: Begins with the biological activity of a substituted analogue of the parent molecule.

Principles: Based on the Hansch equation, but simplifies the process, requiring fewer congeners (chemically related molecules) to be made.

Advantage over Hansch/Free-Wilson Analysis: Eliminates the need for complex equations.

2D QSAR Limitation: Originally time-consuming due to the need to synthesize and test many congeneric compounds.

Initial Approach: Relied on trial and error and did not consider molecular recognition.

Modern Relevance

Question 10

Look at exercise 1

Answer 10

In simple terms, where these groups are attached to a molecule can change how the molecule interacts with electrons, how well it dissolves in fats, and its overall size.
OMe is a strong electron donor but doesn’t change the molecule’s love for fats much.
Cl and Me both make the molecule more fat-loving, with Cl being more effective at this.
In terms of size, Cl and Me are similar, and OMe is the smallest. Adding two Cls (3,4-diCl) makes the molecule even more electron-withdrawing, more fat-loving, and bigger.

Question 11

Modifications on molecules

Answer 11

Depending on which modification makes the molecule more active, scientists can infer whether it needs to fit snugly into a larger space, dissolve well in fats, pull electrons away, or donate electrons to form bonds.

4 OMe has a HBA interaction
4-Me= steric bulk and favouring of aromatic ring
3,4-diCl Activity=electron withdrawing effect and lipophilicity loving

Question 12

Define the concept of a pharmacophore

Answer 12

A pharmacophore describes the three-dimensional orientation of specific steric and electronic features that are necessary for optimal binding interactions with a biological target in order to trigger a desired response.

Question 13

Modern QSAR studies

Answer 13

abstract concept (3 point model), active analogue approach, ligand based drug design and structure based drug design.

Question 14

Active analogue approach

Answer 14

This method involves looking at both molecules that work (active) and those that don’t work (inactive) to figure out what features are necessary for activity.

Computational Energy Minimization for active and low energy conformers are overlaid.

receptor excluded volume is boundaries of all the active molecules.

Question 15

Spatial arrangement

Answer 15

Spatial Arrangement:
Distance Between Features: The distances between these features are specified, which is crucial for fitting into the binding site of the biological target. The distances between R1, R2, and R3 are provided in angstroms (Å).
Perpendicularity: The model specifies that R3 is perpendicular to R1 and R2, which is an important spatial constraint for the molecule’s interaction with its biological target.

Question 16

Exercise 2, making new molecules

Answer 16

Positive ionisable group= positive charge maintains lipophilicity, if there is loss of activty this means it could be a H-bond acceptor or has an ionic interaction
Aromatic rings= If maintained, acts as hydrophobic group, if not loss of activity could be due to pi-pi stacking
If a loss of activity is observed, then the hydrogen-bond acceptor is important for activity instead of replacing with a sulfide which could be interacting with other functional groups.