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 qsar or is qsar different from sar

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 vs qsar how 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

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


Sar vs qsar roadmap

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


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”

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


Sar vs qsar or is qsar different from sar

Numerical

Values

Chemical Grouping by Similarity

Similarity

between structures

Selected similar compounds

Similarity

between points

?


Structural similarity

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

Structurally similar compounds can have very different properties


Example y martin et al 2002 do structurally similar molecules have similar biological activity

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

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

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)


Distances 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

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

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)


Sar vs qsar how could we say there is no difference1

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

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

“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


Neibourhood principle analysis

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

“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 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)


Sar vs qsar how 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.

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


Thank you

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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