QSAR Flashcards
Rational Drug Design
- Identify target disease
- Identify and validate drug target
- Establish screen
- Find a lead compound
- Structure Activity Relationships (SAR)
- Identify the pharmacophore
- Drug design - optimising target interactions
- Drug design - optimising pharmacokinetic properties
- Preclinical trials
- Chemical development and process development
- Patenting and regulatory affairs
- Clinical trials
Rational Drug Design is used to..
- To increase activity and reduce dosage required
* To increase selectivity and reduce side effects
Strategies for rational drug design:
- Vary alkyl and aryl substituents
- Chain extension and contraction
- Ring expansion, contraction and variation
- Isosteric and bioisosteric replacements
- Simplification
- Rigidification
Isosteres
• Replace a functional group with another group of the
same valency
• Leads to more controlled changes in steric and/or
electronic properties but may affect binding and stability
Bioisosteres
- Replace a functional group with another group which retains the same biological activity
- Not necessarily the same valency
The Demand For New Technologies
diagram from slide 7
Structure-Based Drug Design
• Based upon interactions between the lead compound
and the target binding site
• Crystallise target protein with bound lead compound and acquire structure by X-ray crystallography
• Identify binding interactions between ligand and target
(in silico molecular modelling)
• Identify vacant sites for additional binding interactions (in silico)
• Design and ‘fit’ analogues into binding site (in silico)
• Choose lead compounds for synthesis
De-Novo Drug Design
• Drug design based on a knowledge of the binding site
• Crystallise target protein with bound ligand, acquire
structure by X-ray crystallography and identify binding site
• Remove ligand from the target binding site in silico
• Identify potential binding regions within the binding site
• Design a lead compound to fit into the binding site
• Synthesize the lead compound and screen for activity
• Crystallise the lead compound with the target protein and identify the actual binding interactions
• Move to structure-based drug design
Analogues
• Analogues allow the identification of important groups
that are involved in binding to the receptor
• Analogues facilitate identification of the pharmacophore
• Any modifications made to the lead compound may
disrupt binding due to steric or electronic effects
• The easiest analogues to make are those that are made using the lead compound as the substrate
• Possible modifications may be restricted by the presence of other functional groups in the molecule
Structure-Activity Relationships (SAR)
• The aim is to identify which functional groups are important for binding and/or biological activity
Methodology:
• Alter, remove or mask a functional group
• Screen the analogue for activity
• Draw conclusions based upon the screen used (in vitro versus in vivo screens)
• If in vitro activity drops then that implies that the particular group is important for binding
• If in vivo activity in unaffected then that implies that the particular group is not important
Lipinski’s “Rule of Five”
• The “rule of 5” states that: poor absorption or
permeation is more likely when:
• There are more than 5 H-bond donors (expressed as the sum of OHs and NHs)
• The Molecular Weight is over 500
• The LogP is over 5 (or MLogP is over 4.15)
• There are more than 10 H-bond acceptors (expressed as the sum of Ns and Os)
• Compound classes that are substrates for biological transporters are exceptions to the rule.
QSAR
• Quantitative Structure-Activity Relationship
- Relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula
- Requires quantitative measurements of biological activity and physicochemical properties
QSAR • Important properties of drug molecules
- Intermolecular forces (non-covalent interactions)
- Conformational freedom (rigidity/flexibility)
- Lipophilicity (partition coefficient, logP
- Isosteres/bioisoteres
• Most commonly studied in QSAR
- Hydrophobicity of the molecule (log P)
- Hydrophobicity of substituents (pie)
- Electronic properties of substituents (sigma)
- Steric properties of substituents (Es)
• QSAR only valid for compounds within the same structural class
Partition Coefficient P
Partition Coefficient P [Drug in octanol] /
[Drug in water]
log P
- Convenient measure of hydrophobicity
- A dimensionless parameter
- Easily measured in the laboratory - Mlog P
- Can be predicted by calculation - Clog P
Hydrophobicity of Molecule: log P
- Activity of drugs is often related to P
- Binding of drugs to serum albumin, for example
- Straight line implies a limited range of log P
Activity increases as log P increases
i.e. activity is greater for hydrophobic drugs
Hydrophobicity of Molecule: optimum log P
- In many cases there is an optimum log P for activity
- General anaesthetic activity of ethers
- Parabolic curve implies a wider range of log P
Optimum value of log P for activity = log P°
Hydrophobicity of Molecule: log P (2)
- QSAR equations are only applicable to compounds in the same structural class, e.g. ethers
- As an example, however, log Po is similar for anaesthetics of different structural classes, ca. 2.3
- Structures with an approximate log P of 2.3 enter the CNS easily
- potent barbiturates have a log P of approximately 2.0
- By altering the log P value of drugs away from 2.0 it is possible to avoid CNS side effects
Hydrophobicity Constant (pie)
• The hydrophobicity of a substituent relative to hydrogen
• Positive value of pie indicates the substituent is more
hydrophobic than hydrogen
• Negative value of pie indicates the substituent is less
hydrophobic than hydrogen
• Values originally published by Hansch for derivatives of
benzene (benzene Mlog P = 2.13)
• The value of pie is only valid for parent structures
Hydrophobicity Constant
pie - equation
pie x = log Px – log PH
• A QSAR equation may include both P and pie
• P measures the importance of a molecule’s overall
hydrophobicity (relevant to absorption, binding etc)
• Pie identifies specific regions of the molecule which might interact with hydrophobic regions in the binding site
Hammett Substituent Constant (sigma)
• A measure of the electron-withdrawing or
electron-donating properties of a substituent
Steric Factors: Taft’s Steric Factor Es
• Measured by comparing the rates of hydrolysis of substituted aliphatic esters under acidic conditions
Es = log kx - log ko
-kx represents the rate of hydrolysis of a substituted ester
-ko represents the rate of hydrolysis of the parent ester
• Limited to substituents which interact sterically with the tetrahedral transition state for the reaction
• Cannot be used for substituents which interact with the
transition state by resonance or hydrogen bonding
• May undervalue the steric effect of groups in an intermolecular process, i.e. a drug binding to a receptor
Steric Factors: Molar Refractivity MR
A measure of a substituent’s volume
Hansch Equation
• An equation relating various physicochemical properties to the biological activity of a series of compounds
• Usually includes log P, electronic and steric factors
• Start with simple equations and elaborate as more structures are synthesised
• Typical equation for a narrow range of log P is linear
Log (1/C) = k1log P + k2 sigma + k3 Es + k4
• Typical equation for a wide range of log P is parabolic
Log (1/C) = - k1(log P)2 + k2log P + k3 sigma +k4 Es + k5
Hansch Equation
- Example: Adrenergic blocking activity of B-halo-B-arylamines
- Example: Antimalarial activity of phenanthrene aminocarbinols
Hansch Equation - Substituents chosen to satisfy the following criteria:
- A range of values for each physicochemical property
- Values must not be correlated for different properties (i.e. they must be orthogonal in value)
- At least 5 structures are required for each parameter
Craig Plot
- Allows an easy identification of suitable substituents for QSAR analysis including both relevant properties
- Must choose a substituent from each quadrant to include in analogue synthesis to ensure orthogonality
- Choose substituents with a range of values for each property to ensure validity of the study
Topliss Scheme: Rationale
Slide 40
QSAR and Bioisosteres
• Choose substituents with similar physicochemical properties, e.g. CN, NO2 and COMe could be bioisosteres
- Choose based on most important physicochemical property
- COMe and SOMe are similar in sigma p
- SOMe and SO2Me are similar in pie
3D QSAR
- Physical properties are measured for the whole molecule
- Properties are calculated using specialist software
- No experimental constants or measurements are involved
- Properties are known as ‘Fields’
- Steric field - defines the size and shape of the molecule
- Electrostatic field - defines electron rich/poor regions
- Hydrophobic properties are relatively unimportant
3D QSAR Advantages over QSAR
- No reliance on experimental values
- Can be applied to molecules with unusual substituents
- Not restricted to molecules of the same structural class
Univalent isosteres
CH3, NH2, OH, F, CL, SH,
Br, i-Pr
I, t-Bu
Bivalent iosteres
CH2, NH, O, S
trivalent isosteres
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