QSAR

Question 1

6 sources of leads

Answer 1

Nat prod
Synthetic compound collections
Existing drugs
Rational (computer aided) design
Combinatorial synthesis

Question 2

Rational for SAR

Answer 2

1. If group modified and activity stops this group is important for binding
2. …… little effect - group not important
3. If structural change gives increased activity a new interaction with the target site may have been found

Question 3

What types of interations (5)

Answer 3

Ionic
Van der Waals
H bonding
Dipole dipole
Covalent

Question 4

How to probe an alcohol/phenol?

Answer 4

it’s a H bond acceptor so….

make it into an ester

Question 5

How to probe an amine?

Answer 5

Make it into an amide
When it’s ionised - ionic interations
When it’s unionised - H bond donor

Question 6

How to probe an acid?

Answer 6

Make it into an ester
When its ionised - ionic interactions
When its unionised - H bond donor/acceptor

Question 7

How to probe an alkene/aromatic ring?

Answer 7

Reduce or displace

this buffers and stops Van de Waals

Question 8

How to probe alkyl groups?

Answer 8

Change size/shape

Question 9

Pharmacophore definition

Answer 9

Functional groups required for the biological activity of a molecule and their relative position in space

Question 10

Aim of QSAR

Answer 10

to derive mathematical formula that relates biological activity of a series of compounds to particular physio-chemical properties

Question 11

Outcomes of QSAR

4

Answer 11

Medicinal chemists can be confident that a given property plays a role in PK/mechanism of action.
Activities of new analogues predicted
Reduces no of components made
Highlighs new leads

Question 12

Procedure of QSAR

Answer 12

• Synth analogues (common skeleton)
• Evaluate biological activity
• Determine line of best fit (linear regression analysis)
• Evolve to factor in other properties

Question 13

Partition coefficient =

Answer 13

Conc in octanol/conc in water

Question 14

High logP

Answer 14

hydrophobic

Question 15

Generally increasing logP ….. activity

Answer 15

increases … up to a point…. forms a parabola

Question 16

Optimum logP

Answer 16

logPo

Question 17

πx

Answer 17

Substituent hydrophobicity constant

Question 18

Substituent hydrophobicity constant compairs

Answer 18

logP to standard compound eg. benzene

πx = logPx - logPh

Question 19

+ve πx

Answer 19

more hydrophobic than H

Question 20

-ve πx

Answer 20

less hydrophobic than H

Question 21

ClogP

Answer 21

LogP values for compounds using the tabulated π values (without experiment)

Question 22

The difference between logP and π

Answer 22

P is molecules as a whole

π is is region

Question 23

Electroic properties affect… (2)

Answer 23

Ionization and polarity

Question 24

σ

Answer 24

Hammett Substitution Constant

Question 25

Hammett Substitution Constant is a measure of

Answer 25

electron donating/withdrawing effect of a substituent

Question 26

σ is derived how?

Answer 26

Compare dissociation constant where there is one/no substituent on a benzoic acid ring

Question 27

eg EWG

Answer 27

NO2, Cl, CN, CF3

Question 28

eg EDG

Answer 28

Me, Et, Bu

Question 29

σ is +ve

Answer 29

x is EWG

Question 30

σ is -ve

Answer 30

x is EDG

Question 31

For aromatic substituents what positions can we use?

Answer 31

Meta of Para | Because of steric effects apply

Question 32

Steric effects

Answer 32

bulk or shape of moelecule | harder the quantify

Question 33

How to measure steric effects

Answer 33

compare the effect of substiuent on rate of standard reaction such as hydrolysis of ester

Question 34

Es

Answer 34

Tafts steric factor

Question 35

Tafts steric factor

Answer 35

Es = logKx - logKo

Question 36

+ve Es

Answer 36

smaller groups, faster reaction rate

Question 37

-ve Es

Answer 37

larger groups, slower rate if reaction

Question 38

Ref group for Es?

Answer 38

Me

Question 39

QSAR equation relating to several biological factors

Answer 39

Hansch equation

Question 40

Increase carbonyl chain length has what effect on logP

Answer 40

more hydrophobic