Sar vs qsar or is qsar different from sar
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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. SAR is supposed to be not quantitative concept SAR is based on the notion of “similarity” :

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SAR vs QSAR or “is QSAR different from SAR”

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SAR vs QSARor “is QSAR different from SAR”

Joanna Jaworska

Procer & Gamble, Brussels, Belgium

and

Nina Jeliazkova

IPP, Bulgarian Academy of Sciences, Sofia, Bulgaria


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

SAR vs. QSARhow could we say there is no difference ?


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 ?

SAR vs. QSARRoadmap


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”

Similarity : philosophers’ view

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


Numerical

Values

Chemical Grouping by Similarity

Similarity

between structures

Selected similar compounds

Similarity

between points

?


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)


Structurally similar compounds can have very different properties


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


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 ?


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)


Data set 2

Data set 1

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)


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?


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)


Two common things to this point:

Both methods use numerical representation of chemical compounds;

Both methods need to decide which representation to use;

SAR vs. QSARhow could we say there is no difference ?

One more difference : “SAR is a qualitative not a quantitative relationship”

Is this true indeed?


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)


“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


Similar activity values

Activity

Neighbourhood in the descriptor space

Descriptor

“Neibourhood principle” Analysis

Depends on the relationship between the descriptors and activity !!!


“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.


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)


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.

SAR vs. QSARhow could we say there is a difference ?


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


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