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Numerous ligand-based drug discovery projects are based on structure-activity relationship (SAR) analysis, such as Free-Wilson (FW) or matched molecular pair (MMP) analysis. Intrinsically they assume linearity and additivity of substituent contributions. These techniques are challenged by nonadditivity (NA) in protein-ligand binding where the change of two functional groups in one molecule results in much higher or lower activity than expected from the respective single changes. Identifying nonlinear cases and possible underlying explanations is crucial for a drug design project since it might influence which lead to follow. By systematically analyzing all AstraZeneca (AZ) inhouse compound data and publicly available ChEMBL25 bioactivity data, we show significant NA events in almost every second assay among the inhouse and once in every third assay in public data sets. Furthermore, 9.4% of all compounds of the AZ database and 5.1% from public sources display significant additivity shifts indicating important SAR features or fundamental measurement errors. Using NA data in combination with machine learning showed that nonadditive data is challenging to predict and even the addition of nonadditive data into training did not result in an increase in predictivity. Overall, NA analysis should be applied on a regular basis in many areas of computational chemistry and can further improve rational drug design.
Keywords
Nonadditivity analysis, structure-activity relationship, matched molecular pair analysis, experimental uncertainty, machine learning, support vector machine, random forest.
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CURRENT STATUS: Under Review
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Posted 01 May, 2021
Editorial decision: Minor revision
On 01 May, 2021
Review #1 received
Received 30 Apr, 2021
Review #2 received
Received 19 Apr, 2021
Reviewer #2 agreed
On 18 Apr, 2021
Reviewers invited
Invitations sent on 17 Apr, 2021
Reviewer #1 agreed
On 17 Apr, 2021
Editor assigned
On 15 Apr, 2021
Submission checks complete
On 15 Apr, 2021
Editor invited
On 15 Apr, 2021
This version was not preprinted
Version (no preprint)
Posted 08 Feb, 2021
Editorial decision: Major revision
On 08 Feb, 2021
Review #2 received
Received 06 Feb, 2021
Review #1 received
Received 16 Jan, 2021
Reviewer #2 agreed
On 07 Jan, 2021
Reviewers invited
Invitations sent on 05 Jan, 2021
Reviewer #1 agreed
On 05 Jan, 2021
Editor assigned
On 03 Jan, 2021
Submission checks complete
On 03 Jan, 2021
Editor invited
On 03 Jan, 2021
This version was not preprinted
Version 1
Posted 16 Dec, 2020
No community comments so far
Editorial decision: Revise before peer review
On 18 Dec, 2020
Editor assigned
On 15 Dec, 2020
Editor invited
On 15 Dec, 2020
Submission checks complete
On 12 Dec, 2020
First submitted
On 09 Dec, 2020
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This preprint is under consideration at Journal of Cheminformatics. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research article
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version (no preprint)
Posted 01 May, 2021
Editorial decision: Minor revision
On 01 May, 2021
Review #1 received
Received 30 Apr, 2021
Review #2 received
Received 19 Apr, 2021
Reviewer #2 agreed
On 18 Apr, 2021
Reviewers invited
Invitations sent on 17 Apr, 2021
Reviewer #1 agreed
On 17 Apr, 2021
Editor assigned
On 15 Apr, 2021
Submission checks complete
On 15 Apr, 2021
Editor invited
On 15 Apr, 2021
This version was not preprinted
Version (no preprint)
Posted 08 Feb, 2021
Editorial decision: Major revision
On 08 Feb, 2021
Review #2 received
Received 06 Feb, 2021
Review #1 received
Received 16 Jan, 2021
Reviewer #2 agreed
On 07 Jan, 2021
Reviewers invited
Invitations sent on 05 Jan, 2021
Reviewer #1 agreed
On 05 Jan, 2021
Editor assigned
On 03 Jan, 2021
Submission checks complete
On 03 Jan, 2021
Editor invited
On 03 Jan, 2021
This version was not preprinted
Version 1
Posted 16 Dec, 2020
No community comments so far
Editorial decision: Revise before peer review
On 18 Dec, 2020
Editor assigned
On 15 Dec, 2020
Editor invited
On 15 Dec, 2020
Submission checks complete
On 12 Dec, 2020
First submitted
On 09 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Numerous ligand-based drug discovery projects are based on structure-activity relationship (SAR) analysis, such as Free-Wilson (FW) or matched molecular pair (MMP) analysis. Intrinsically they assume linearity and additivity of substituent contributions. These techniques are challenged by nonadditivity (NA) in protein-ligand binding where the change of two functional groups in one molecule results in much higher or lower activity than expected from the respective single changes. Identifying nonlinear cases and possible underlying explanations is crucial for a drug design project since it might influence which lead to follow. By systematically analyzing all AstraZeneca (AZ) inhouse compound data and publicly available ChEMBL25 bioactivity data, we show significant NA events in almost every second assay among the inhouse and once in every third assay in public data sets. Furthermore, 9.4% of all compounds of the AZ database and 5.1% from public sources display significant additivity shifts indicating important SAR features or fundamental measurement errors. Using NA data in combination with machine learning showed that nonadditive data is challenging to predict and even the addition of nonadditive data into training did not result in an increase in predictivity. Overall, NA analysis should be applied on a regular basis in many areas of computational chemistry and can further improve rational drug design.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12
This preprint is available for download as a PDF.
This is a list of supplementary files associated with this preprint. Click to download.
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