Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

PSFC2 > QSAR > Flashcards

QSAR Flashcards

1
Q

Rational Drug Design

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Rational Drug Design is used to..

A
  • To increase activity and reduce dosage required

* To increase selectivity and reduce side effects

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Strategies for rational drug design:

A
  • Vary alkyl and aryl substituents
  • Chain extension and contraction
  • Ring expansion, contraction and variation
  • Isosteric and bioisosteric replacements
  • Simplification
  • Rigidification
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Isosteres

A

• 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Bioisosteres

A
  • Replace a functional group with another group which retains the same biological activity
  • Not necessarily the same valency
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

The Demand For New Technologies

A

diagram from slide 7

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Structure-Based Drug Design

A

• 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

De-Novo Drug Design

A

• 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Analogues

A

• 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Structure-Activity Relationships (SAR)

A

• 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Lipinski’s “Rule of Five”

A

• 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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

QSAR

• Quantitative Structure-Activity Relationship

A
  • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

QSAR • Important properties of drug molecules

A
  • Intermolecular forces (non-covalent interactions)
  • Conformational freedom (rigidity/flexibility)
  • Lipophilicity (partition coefficient, logP
  • Isosteres/bioisoteres
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

• Most commonly studied in QSAR

A
  • 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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Partition Coefficient P

A

Partition Coefficient P [Drug in octanol] /

[Drug in water]

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

log P

A
  • Convenient measure of hydrophobicity
  • A dimensionless parameter
  • Easily measured in the laboratory - Mlog P
  • Can be predicted by calculation - Clog P
17
Q

Hydrophobicity of Molecule: log P

A
  • 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

18
Q

Hydrophobicity of Molecule: optimum log P

A
  • 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°

19
Q

Hydrophobicity of Molecule: log P (2)

A
  • 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
20
Q

Hydrophobicity Constant (pie)

A

• 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

21
Q

Hydrophobicity Constant

pie - equation

A

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

22
Q

Hammett Substituent Constant (sigma)

A

• A measure of the electron-withdrawing or

electron-donating properties of a substituent

23
Q

Steric Factors: Taft’s Steric Factor Es

A

• 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

24
Q

Steric Factors: Molar Refractivity MR

A

A measure of a substituent’s volume

25
Q

Hansch Equation

A

• 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

26
Q

Hansch Equation

A
  • Example: Adrenergic blocking activity of B-halo-B-arylamines
  • Example: Antimalarial activity of phenanthrene aminocarbinols
27
Q

Hansch Equation - Substituents chosen to satisfy the following criteria:

A
  • 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
28
Q

Craig Plot

A
  • 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
29
Q

Topliss Scheme: Rationale

A

Slide 40

30
Q

QSAR and Bioisosteres

A

• 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
31
Q

3D QSAR

A
  • 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
32
Q

3D QSAR Advantages over QSAR

A
  • No reliance on experimental values
  • Can be applied to molecules with unusual substituents
  • Not restricted to molecules of the same structural class
33
Q

Univalent isosteres

A

CH3, NH2, OH, F, CL, SH,
Br, i-Pr
I, t-Bu

34
Q

Bivalent iosteres

A

CH2, NH, O, S

35
Q

trivalent isosteres

A

draw

PSFC2 (31 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions