SAR vs QSAR or is QSAR different from SAR - PowerPoint PPT Presentation

1 / 21
About This Presentation
Title:

SAR vs QSAR or is QSAR different from SAR

Description:

IPP, Bulgarian Academy of Sciences, Sofia, Bulgaria. SAR vs. QSAR ... Possible solution : look for the most discriminative information ... – PowerPoint PPT presentation

Number of Views:529
Avg rating:3.0/5.0
Slides: 22
Provided by: ninani
Category:

less

Transcript and Presenter's Notes

Title: SAR vs QSAR or is QSAR different from SAR


1
SAR vs QSAR or is QSAR different from SAR
Joanna Jaworska Procer Gamble, Brussels,
Belgium and Nina Jeliazkova IPP, Bulgarian
Academy of Sciences, Sofia, Bulgaria

2
SAR vs. QSARhow could we say there is no
difference ?
  • SAR is supposed to be not quantitative concept
  • SAR is based on the notion of similarity
  • Similar compounds have similar activity
  • Dissimilar compounds have dissimilar activity
  • QSAR aims to derive a quantitative model of the
    activity

3
SAR vs. QSARRoadmap
  • What similarity means? A philosophers view and
    implications to the toxicology
  • Are the basic tenets of SAR true ?
  • What do similarity measures measure ?
  • How does the similarity measure relate to QSAR
    modeling ?

4
Similarity philosophers view
  • exploiting the similarity concept is a sign of
    immature science (Quine)
  • it is ill defined to say A is similar to B and
    it is only meaningful to say
  • A is similar to B with respect to C

implications for toxicology A chemical A
cannot be similar to a chemical B in absolute
terms but only with respect to some measurable
key feature
5
Chemical Grouping by Similarity
Similarity between structures
Selected similar compounds
Similarity between points
?
6
Structural similarity
  • Does not imply always similarity in activity
  • Martin et al. 2002 J.Med.Chem 45,4350-58
  • Does not always imply similarity in descriptors
  • Kubinyi, H., Chemical Similarity and Biological
    activity (with permission of the author)

7
Structurally similar compounds can have very
different properties
8
Example Y.Martin et al ( 2002) Do structurally
similar molecules have similar biological
activity ?
  • Set of 1645 chemicals with IC50s for monoamine
    oxidase inhibition
  • Daylight fingertips 1024 bits long ( 0-7 bonds)
  • Using Tanimoto coeff with a cut off value 0f 0.85
    only 30 of actives were detected

Cutoff values of actives detected False
positives
J. Med. Chem. 2002,45,4350-4358
9
How else to measure chemical similarity ?
  • Describe chemical compounds with a set of
    numerical values ( fingerprints, diverse
    descriptors, field values, etc.)
  • Set up some measure between values (Euclidean
    distance, Tanimoto distance, Carbo similarity
    index, etc.)

What do we actually measure ? And how it is
related to the activity ?
10
What do we measure ?
The distance between numerical representations of
chemical compounds
  • A few warnings
  • The numerical representation is not unique
  • The numerical representation includes only part
    of all the information about the compound
  • A distance measure reflects closeness only if
    the data holds specific assumptions
  • (next slide - example)

11
Distances - example
by Euclidean distance we will decide that the red
point is closer to the data set 2, while a human
will note that it belongs to the data set 1.
  • Distances give results which are not always
    expected intuitively
  • Be aware of the assumptions behind distances
    (e.g. Euclidean distance gives good results with
    normally distributed data in orthogonal space)

12
How do we represent a chemical compound ?
Fingerprints, Descriptors (more than 3000
available), electron density, various fields, etc.
All representations lose information. We should
ensure this information is not important. How?
13
Finding important information
  • A problem not unique to (Q)SAR
  • Lot of methods available
  • Most popular (e.g. PCA ) not the best

Possible solution look for the most
discriminative information (example descriptors
which provide best discrimination between active
and inactive compounds)
14
SAR vs. QSARhow could we say there is no
difference ?
  • Two common things to this point
  • Both methods use numerical representation of
    chemical compounds
  • Both methods need to decide which representation
    to use

One more difference SAR is a qualitative not a
quantitative relationship Is this true indeed?
15
Similarity and Activity
  • Proximity with respect to descriptors does not
    necessary mean proximity with respect to the
    activity (example)
  • This is only true if a linear relationship holds
    between descriptors and activity (examples)
  • The linear relationship is only a special case,
    given the complexity of biochemical interactions.
    Its use should be justified in every specific
    case
  • Structural similarity should be used with care
    (examples)

16
Neighbourhood principle
  • Molecules in the same local region
    (neighbourhood) of a descriptor space tend to
    have similar values of a desired property
  • Contradictory evidence exists both supporting
    and rejecting

17
Neibourhood principle Analysis
Depends on the relationship between the
descriptors and activity !!!
18
Neighbourhood principle Lessons
  • In order to apply the neighbourhood principle
    the TYPE of the relationship between descriptor
    and activity should be known
  • The neighbourhood principle is genuine only if
    the relationship is LINEAR
  • The linear relationship is only a simple special
    case, given the complexity of biochemical
    interactions. Its use SHOULD BE JUSTIFIED in
    every specific case.

19
SAR vs QSAR
  • SAR is based on the similarity principle
  • The principle is assumed, but in the reality it
    is not always true
  • Similarity of structures
  • Similarity of descriptors
  • The authenticity depends on the type of the
    relationship between descriptors (numerical
    representation of chemicals) and activity
  • The type of the relationship should be known (or
    derived)

20
SAR vs. QSARhow could we say there is a
difference ?
  • Three common things to this point
  • Both methods use numerical representation of
    chemical compounds
  • Both methods need to decide which representation
    to use
  • Both methods need to derive the relationship
    between numerical representation (descriptors,
    etc.) and activity.

21
Thank you!
When you can measure what you are speaking about,
and express it in numbers, you know something
about it but when you cannot measure it, when
you cannot express it in numbers, your knowledge
is of a meager and unsatisfactory kind it may
be the beginning of knowledge, but you have
scarcely advanced to the stage of
science. William Thomson, Lord Kelvin
Write a Comment
User Comments (0)
About PowerShow.com