QSAR Flashcards
6 sources of leads
Nat prod Synthetic compound collections Existing drugs Rational (computer aided) design Combinatorial synthesis
Rational for SAR
- If group modified and activity stops this group is important for binding
- …… little effect - group not important
- If structural change gives increased activity a new interaction with the target site may have been found
What types of interations (5)
Ionic Van der Waals H bonding Dipole dipole Covalent
How to probe an alcohol/phenol?
it’s a H bond acceptor so….
make it into an ester
How to probe an amine?
Make it into an amide
When it’s ionised - ionic interations
When it’s unionised - H bond donor
How to probe an acid?
Make it into an ester
When its ionised - ionic interactions
When its unionised - H bond donor/acceptor
How to probe an alkene/aromatic ring?
Reduce or displace
this buffers and stops Van de Waals
How to probe alkyl groups?
Change size/shape
Pharmacophore definition
Functional groups required for the biological activity of a molecule and their relative position in space
Aim of QSAR
to derive mathematical formula that relates biological activity of a series of compounds to particular physio-chemical properties
Outcomes of QSAR
4
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
Procedure of QSAR
- Synth analogues (common skeleton)
- Evaluate biological activity
- Determine line of best fit (linear regression analysis)
- Evolve to factor in other properties
Partition coefficient =
Conc in octanol/conc in water
High logP
hydrophobic
Generally increasing logP ….. activity
increases … up to a point…. forms a parabola
Optimum logP
logPo
πx
Substituent hydrophobicity constant
Substituent hydrophobicity constant compairs
logP to standard compound eg. benzene
πx = logPx - logPh
+ve πx
more hydrophobic than H
-ve πx
less hydrophobic than H
ClogP
LogP values for compounds using the tabulated π values (without experiment)
The difference between logP and π
P is molecules as a whole
π is is region
Electroic properties affect… (2)
Ionization and polarity
σ
Hammett Substitution Constant
Hammett Substitution Constant is a measure of
electron donating/withdrawing effect of a substituent
σ is derived how?
Compare dissociation constant where there is one/no substituent on a benzoic acid ring
eg EWG
NO2, Cl, CN, CF3
eg EDG
Me, Et, Bu
σ is +ve
x is EWG
σ is -ve
x is EDG
For aromatic substituents what positions can we use?
Meta of Para
Because of steric effects apply
Steric effects
bulk or shape of moelecule
harder the quantify
How to measure steric effects
compare the effect of substiuent on rate of standard reaction such as hydrolysis of ester
Es
Tafts steric factor
Tafts steric factor
Es = logKx - logKo
+ve Es
smaller groups, faster reaction rate
-ve Es
larger groups, slower rate if reaction
Ref group for Es?
Me
QSAR equation relating to several biological factors
Hansch equation
Increase carbonyl chain length has what effect on logP
more hydrophobic
