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Medicinal Chemistry/ CHEM 458/658
Chapter 3- SAR and QSAR
Bela TorokDepartment of Chemistry
University of Massachusetts BostonBoston, MA
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Introduction
• Structure-Activity Relationship (SAR)
- similar structures –similar effects
- more potency or improved side effects
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• Quantitative Structure-Activity Relationship (QSAR)
- similar structures –similar effects but uses parameters todescribe the potency
- parameters – anything (related to drug action) that can berepresented by a numerical values
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• Usually go through minor changes on the lead structure- the and shape of the carbon skeleton- the nature and degree of substitution- stereochemistry
Structure-Activity Relationship (SAR)
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• Changing size and shape
- number of methylene groups in chains and rings
- increasing or decreasing the degree of unsaturation
- introducing or removing a ring system
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Structure-Activity Relationship (SAR)
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• Changing the number of methylene groups
- increases lipophilicity (increased activity)- decreases water solubility (decreased activity)- aliphatic compounds – micelle formation – no selective binding
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Structure-Activity Relationship (SAR)
antipsychotic antidepressant
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• Changing the degree of unsaturation
- increasing – rigidity - E-Z isomers might complicate the picture- more sensitivity- increased toxicity
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Structure-Activity Relationship (SAR)
1 : 30 antipsychotic antidepressant
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• Introduction or removal of a ring system- addition – size increase, shape changes (effect mostlyunpredictable
- increasing size – better fills the hydrophobic pocket
- small ring to substitute C=C double bonds - stability
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Structure-Activity Relationship (SAR)
antidepressant
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Structure-Activity Relationship (SAR)
• Introduction of an aromatic ring- increases rigidity, shape changes resistance toward metabolism might improve
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Structure-Activity Relationship (SAR)
• Modifying the ring system of drugs of natural origin- fine tuning of effect and side effects
more potent(highly addictive)
less potent
less potent(less addictive)
equally potent(less addictive)
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• Introduction of new substituentsmethyl groups increases lipophilicity
steric hindrance – might block activity
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Structure-Activity Relationship (SAR)
Compound Structure P Analogue Structure P
benzene 135 toluene 490
acetamide CH3CONH2 83 propionamide CH3CH2CONH2 360
urea NH2CONH2 15 N-methylurea CH3NHCONH2 44
1 3.7
0
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Structure-Activity Relationship (SAR)
• Introduction of methyl group- methyl group on aromatic rings – increased rate of metabolism
- demethylation – easy on heteroatoms, especially on N+, S+
- reduce the rate of metabolism
- reduce unwanted side effects
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Structure-Activity Relationship (SAR)
• Introduction of halogens
Mostly F and Cl - C-X bond stability - reactivity
CF3 is also very popular
location
OF
OHO
O
OCH3
NHCH3
O
CF3
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Structure-Activity Relationship (SAR)
• Introduction of hydroxyl groups
Mostly to increase hydrophilic character
Phenolic OH is special
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Structure-Activity Relationship (SAR)
• Introduction of basic groups
Mostly to increase binding via H-bonding/acid baseinteractions
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Structure-Activity Relationship (SAR)
• Introduction of COOH and SO3H groups
Mostly to increase binding via H-bonding/acid baseinteractions – in vivo salt formationintroduction to small leads – usually changes the activity
SO3H – no significant effect except faster excretion
Other S groups are rare - metabolism
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• Changes the existing substituents of a lead
isosteres - bioisosteres
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Structure-Activity Relationship (SAR)
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Structure-Activity Relationship (SAR)
• Changes the existing substituents of a lead
isosteres - bioisosteres
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• Case Study: SAR investigation to discover potent geminalbisphosphonates
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Structure-Activity Relationship (SAR)
first generation
second generation
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Structure-Activity Relationship (SAR)
• Case Study: SAR investigation to discover potent geminalbisphosphonates
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Structure-Activity Relationship (SAR)
• Case Study: SAR investigation to discover potent geminalbisphosphonates
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Structure-Activity Relationship (SAR)
• Case Study:SAR investigation to discover potent geminalbisphosphonates
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• Case Study: SAR investigation to discover potent geminalbisphosphonates
Structure-Activity Relationship (SAR)
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Quantitative Structure-Activity Relationship (QSAR)
• QSAR – mathematical relationship (equations)biological effect vs. physicochemical parameters
- lipophilicity- electron distribution- shape- size- partition coefficients- Hammett or Tafts constants
Biological activity = F {parameters (s)}
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• Regression Analysis
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Quantitative Structure-Activity Relationship (QSAR)
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• Lipophilic parameters
Partition coefficient
log (1/C) = k1 log P +k2
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Quantitative Structure-Activity Relationship (QSAR)
(1) Toxicity of alcohols to red spiders:log (1/C) = 0.69 log P + 0.16 r = 0.979, n = 14, s = 0.087
(2) The binding of misc. neutral molecules to bovine serum:log (1/C) = 0.75 log P +2.30 r = 0.96, n = 42, s = 0.159
(3) The binding of misc. neutral molecules to haemoglobin:log (1/C) = 0.71 log P +1.51 r = 0.95, n = 17, s = 0.16
(4) Inhibition of phenols on the conversion of P-450 to P-420 cytochromes:log (1/C) = 0.57 log P +036 r = 0.979, n = 13, s = 0.132
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Quantitative Structure-Activity Relationship (QSAR)
• Lipophilic parameters
Partition coefficient – often parabolic
log (1/C) = -k1 (log P)2 + k2log P + k3
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Quantitative Structure-Activity Relationship (QSAR)
• Lipophilic parameters
hypnosis (mice) with barbiturates
log (1/C) = - 0.44 (log P)2 + 1.58 log P + 1.93 (r=0.969)
Hansch – logP ~ 2 hypnotic (CNS drug)
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Quantitative Structure-Activity Relationship (QSAR)
• Lipophilic parameters
lipophilic substituent constants (π) (or hydrophobic)contribution of substituents to P
π = logPX – logPH
π = logP(C6H5Cl) – logP(C6H6) = 2.84 – 2.13 = 0.71
π = π (substituent 1) + π (substituent 2) …..+ π (substituent n)
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Quantitative Structure-Activity Relationship (QSAR)
• Lipophilic parameters
lipophilic substituent constants (π)
log (1/C) vs π high r and low s – important contributor
Substituent X Aliphatic systems R-X
- H 0.00 0.00 0.00 0.00- CH3 0.50 0.56 0.52 0.49- F - 0.17 0.14 0.31- Cl 0.39 0.71 0.54 0.93- OH - 1.16 - 0.67 0.11 - 0.87- NH2 - 1.23 - 0.46 - 1.63- NO2 - 0.28 - 0.39 0.50- OCH3 0.47 - 0.02 0.18 - 0.12
XX O2N XHO
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Quantitative Structure-Activity Relationship (QSAR)
• Lipophilic parameters
distribution coefficients (D)
ionization
for acids
for bases
D =[ HAorganic ]
[ H+aqueous ] + [ A-aqueous ]
log (P/D-1) = pH -pKa
log (P/D-1) = pKa - pH
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• Electronic parameters
The Hammett constant (σ)
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Quantitative Structure-Activity Relationship (QSAR)
σx = log KxK
σ x = log Kx - log K
σ x = pK - pKx
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Quantitative Structure-Activity Relationship (QSAR)
• Electronic parameters
The Hammett constant (σ)
log (1/C) = 2.282 σ - 0.348
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Quantitative Structure-Activity Relationship (QSAR)
• Steric parameters
The Taft steric parameter (Es)
Es = logk (XCH2COOCH3)
k (CH3COOCH3)= k(XCH2COOCH3) - k(CH3COOCH3)
log BR = 0.440Es - 2.204 (n=30; s=0.37; r= 0.886)
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Quantitative Structure-Activity Relationship (QSAR)
• Steric parameters
Molar refractivity (MR)
additive – functional groups
MR =(n2 - 1) M
(n2+2) ρ
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Quantitative Structure-Activity Relationship (QSAR)
• Hansch analysis
drug activity vs. measurable chemical propertiesmultiparameter approach
two stages: - transport to the site of action- binding to the target site
log 1/C = k1(partition parameter)+k2(electronic parameter)+k3(steric parameter)+k4
log 1/C = k1P - k2P2+k3σ+k4Es+ k5
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Quantitative Structure-Activity Relationship (QSAR)
• Hansch analysis
Accuracy :
- Greater number of analogs – n=5x (x= number of parameters)- biological data- the choice of parameters
Use:- Asses the factors controlling the activity- predict optimum activity (ideal parameter values)
Sources of parameters- CRC, CAS, Merck Index, etc.
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Quantitative Structure-Activity Relationship (QSAR)
• Craig plots
Use with Hansch analysis:
log 1/C = 2.67π – 2.56σ + 3.92