Revising the Topliss Decision Tree
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Revising the Topliss decision tree
…based on 30 years of medicinal chemistry literature
Noel O’Boyle and Roger Sayle NextMove Software
Jonas Boström AstraZeneca
248th ACS National Meeting Aug 2014
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http
://ww
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Topliss Tree for Substituted Phenyl
Topliss, J. G. Utilization of Operational Schemes for Analog Synthesis in Drug Design. J. Med. Chem. 1972, 15, 1006–1011.
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Features of the Topliss Tree
• Maximize the chances of synthesizing the most potent compound in the series as soon as possible
• Based on inferring Hansch structure-activity relationship from relative potencies of R groups
– Electronic (σ), hydrophobic (π), steric (Es)
• General scheme
– for any target
– for any scaffold
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ChEMBL Bioactivity database
• July 2008 - ChEMBL established with Wellcome Trust grant
– John Overington, EMBL-EBI
• Open access source of bioactivity data abstracted from the literature
– Chemical structures, activity values, activity type, assay description, journal article name, target
– www.ebi.ac.uk/chembl/
Gaulton et al. Nucleic Acids Res. 2012, 40, D1100
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ChEMBL Bioactivity database
• ChEMBL 19 – July 2014
– 57k papers
• 94% from Bioorg. Med. Chem. Lett., J. Med. Chem., J. Nat. Prod., Bioorg. Med. Chem., Eur. J. Med. Chem., Antimicrob. Agents Chemother., Med. Chem. Res.
– 1.4 million compounds with 12 million activities
– 1.1 million assays against 10k targets
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0
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1977 1982 1987 1992 1997 2002 2007 2012
Co
un
t
Year
Number of articles extracted from a particular year
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Matched (Molecular) series
• Recent concept in cheminformatics (*)
– … not so recent in medicinal chemistry
• Series of structural analogs
– same scaffold
– different R groups at a single position
* “Matching molecular series” introduced by Wawer and Bajorath J. Med. Chem. 2011, 54, 2944
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Matched Series of length 3
[Cl, F, NH2]
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Matched Series of length 3
[4-Cl-Ph, 4-F-Ph, 4-NH2-Ph]
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Ordered Matched Series
[4-Cl-Ph > 4-F-Ph > 4-NH2-Ph]
3.5
2.1
1.6
pIC50
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1
10
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1000
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1000000
2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50
Fre
qu
en
cy
Series length
Matched series in ChEMBL19 IC50 binding assays
Length 2: 240,967 212,494 Length 3: 59,753 52,666 Length 4: 27,779 24,306 Length 5: 15,892 13,834 Length 6: 10,619 9,203
Method described in O’Boyle, Boström, Sayle, Gill. Using Matched Molecular Series as a Predictive Tool To Optimize Biological Activity. J. Med. Chem. 2014, 57, 2704.
(ChEMBL16)
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0
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9000Fr
eq
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ncy
R Groups sorted by frequency
Analysis of the 16268 matched series containing at least 4 substituted phenyls
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Find R Groups that increase activity
A > B
Query A > B > C C > A > B D > A > B > C D > A > C > B E > D > A > B …
R Group Observations
Obs that
increase
activity
% that
increase
activity
D 3 3 100
E 1 1 100
C 4 1 25
… … …
O’Boyle, Boström, Sayle, Gill. Using Matched Molecular Series as a Predictive Tool To Optimize Biological Activity. J. Med. Chem. 2014, 57, 2704.
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Example
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Example II
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Topliss Decision Tree
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Topliss Decision Tree
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Topliss Decision Tree
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Topliss Decision Tree
(1st if lower cutoff)
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Topliss Decision Tree
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Topliss Decision Tree
(20th)
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Topliss Decision Tree
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Topliss Decision Tree
(21st) “Assuming that the –σ effect is the most probable explanation…”
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Topliss Decision Tree
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Topliss Decision Tree
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Topliss Decision Tree
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Topliss Decision Tree
*
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Matsy Decision Tree
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Matsy Decision Tree (Take II)
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Target specific subsets
4-Cl > H
Everything Kinases Class A GPCRs
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Account for Lipophilic Efficiency
• ΔLiPE = ΔpIC50 – ΔLogP
• The “%>” value is based on the number of times a particular R group has greater pIC50
– i.e. ΔpIC50 > 0
• Redefine it to only include cases where the increase in pIC50 was larger than any increase in LogP
– i.e. ΔpIC50 > 0 and ΔLiPE > 0
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4-Cl > H
ΔLiPE > 0
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ΔLiPE > 0
3,4-diCl > 4-Cl > H
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Data-driven approach
• Not limited to the two trees in the Topliss paper
• All predictions backed by experimental data
– Can drill-down into the data, look at targets, scaffolds
– Can restrict experimental data used to particular targets, use in-house data rather than ChEMBL
• Does not explain why, only that it happens
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Conclusions
• In the main, the Topliss Tree is supported by published data
– Largest difference is recommendation of 4-OMe rather than 4-OH
– Suggestion of 4-CF3 is also problematic
• We have generated the corresponding ‘Matsy Tree’ derived from experimental data
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drag-and-drop interface to Matsy
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Revising the Topliss decision tree …based on 30 years of medicinal
chemistry literature
Using Matched Molecular Series as a Predictive Tool To Optimize Biological
Activity J. Med. Chem. 2014, 57, 2704.
Want to hear more? Poster COMP 394 Tuesday 6:00-8:00pm Marriott Marquis Interested in an evaluation copy of Matsy? Come by our booth