analyzing building blocks diversity for dna …...cresset user group meeting nik stiefl & finton...
TRANSCRIPT
![Page 1: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/1.jpg)
Cresset User Group MeetingNik Stiefl & Finton Sirockin, Novartis2016.06.16
Analyzing Building Blocks Diversity for DNA Encoded Library Design
![Page 2: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/2.jpg)
DNA Encoded Libraries (DEL)
Building blocks selection process
Capping group selection• 2D fingerprints• Cresset fields
Caveats
Conclusion
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public2
Outline
![Page 3: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/3.jpg)
DEL technology uses DNA oligonucleotides to record the combinatorial synthesis of organic molecules...
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public3
Dimer library, W x X compounds• Pos 1: W building blocks, A1 to AW
• Pos 2: X building blocks, B1 to BX
W reaction vessels 1 reaction vessel X reaction vessels X reaction vessel
X reaction vessels 1 vessel
Trimer library
W x X x Y compounds
Tetramer library
W x X x Y x Z compounds
![Page 4: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/4.jpg)
ExtractBBs
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public4
Building Blocks selection processGeneral process
Diversity
Price
Chemicalintuition
Stiefl, N.; Gedeck, P.; Chin, D.; Hunt, P.; Lindvall, M.; Spiegel, K.; Springer, C.; Biller, S.; Buenemann, C.; Kanazawa, T.; Kato, M.; Lewis, R.; Martin, E.; Polyakov, V.; Tommasi, R.; van Drie, J.; Vash, B.; Whitehead, L.; Xu, Y.; Abagyan, R.; Raush, E.; Totrov, M. FOCUS — Development of a Global Communication and Modeling Platform for Applied and Computational Medicinal Chemists. J. Chem. Inf. Model. 2015, 55 (4), 896–908.
Internal Vendors
![Page 5: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/5.jpg)
Project libraries DNA Encoded Libraries# of building blocks 10-50 100s – 1000s
Design principle Target knowledge Diversity & Density
Priority on Scaffold Combinator’ics’
Property space Target driven and limited Simultaneous SAR andphysico-chemical exploration
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public5
Building Blocks selection processWhat makes DNA Encoded Libraries different ?
![Page 6: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/6.jpg)
Atom properties (atomic number, degree, number pi electrons) and inter-atom distances encode molecules
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public6
2D descriptionsExample: Atom Pairs[1]
O
N
N
ON
N
AP : 0.58
[1] Sheridan, R. P.; Miller, M. D.; Underwood, D. J.; Kearsley, S. K. J. Chem. Inf. Comput. Sci. 1996, 36, 128 – 136
O
N
N
![Page 7: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/7.jpg)
Modifying atom invariants and Rooted Fingerprints [1]
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public7
2D descriptionsInfluence of reacting group on descriptors
O
N
N
ON
N
N
NN
N
42C
N
N42CN
N
AP : 0.58
AP : 1.0
APMI : 0.43APRooted : 0.29
APMI : Atom Pairs Modified Invariant[1] Vulpetti, A.; Hommel, U.; Landrum, G.; Lewis, R.; Dalvit, C. J. Am. Chem. Soc., 2009, 131, 12949-12959
![Page 8: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/8.jpg)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public8
Capping groups specific fingerprintsClockwise : AP vs. APMI ; APRooted vs. APMI ; APRooted vs. AP.
Similarity plotsof pairs of1832 aldehydes
![Page 9: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/9.jpg)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public9
From 2D to 3DBrainstorming in Novartis
![Page 10: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/10.jpg)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public10
The Cauliflower™(Frédéric Berst - Novartis)
Distributing pharmacophores (Cresset fields) in space
HN
R3
HN
R3
HN
R3
HN
R3
HydrophobicPolar +Polar –Space aroundderivatisation point
Diverse (2D) BBs
HN
Distributingdifferent PH4
(fields) types asevenly as possible
in space
![Page 11: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/11.jpg)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public11
Le «Caulitree»
![Page 12: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/12.jpg)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public12
Building Blocks clustering with Cresset technologyWorkflow developed by Paolo Tosco (Cresset)
BBs preparation
• Cleaning• Reacting group labelling
BBs conformations
• 3D coordinates generation and protonation• Conformations generation
BBs Cressetprocessing
• Alignment on bond vector• Cresset similarity matrix calculation• Clustering
BBs selection
• Cluster visualisation• BBs selection by clusters using multiple parameters (price,
reactivity profiling, density of in-house availablility, etc)
Non Cresset
CRESSET
![Page 13: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/13.jpg)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public13
Pharmacophore distribution clusteringHelp chemists choosing BBs to maximise pharmacophore coverage and BB attractiveness
Example clusters from the processing of 1832 aldehydes ( ~ 12 hours on a cluster)
![Page 14: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/14.jpg)
Minor influence on 2D description depending on BB sizeand functionality
Major influence on Cresset fields ( transform withrespect to resulting product)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public14
Handling the reactive handleFunctional group vs. isotope labelling
AP vs. APMI
![Page 15: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/15.jpg)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public15
Handling the reactive handleReplace vs. add (“CC” vs. “CCC”)
O
N
N
R
N
N
N
N
R
![Page 16: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/16.jpg)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public16
Pharmacophore spacesIdentifying missing spots
1300 NAS reagents aligned on the derivatisation vector. Top and side viewsDisc-like electropositive density with obvious hole on top and bottom
![Page 17: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/17.jpg)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public17
2D vs 3D - does it make a difference?Cresset vs. APRooted
Cresset: 0.92 APRooted: 0.33
Cresset: 0.90 APRooted: 0.40
![Page 18: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/18.jpg)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public18
2D vs 3D - does it make a difference?Cresset vs. APRooted
Cresset: 0.57 APRooted: 0.88
Cresset: 0.66 APRooted: 1.00
Cresset: 0.39 APRooted: 0.85
![Page 19: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/19.jpg)
Reactive group treatment
Tautomers
Capping group only (for the moment)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public19
Caveats
![Page 20: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/20.jpg)
Identification of unexplored exit vector space (branches in the caulitree)
To be combined with spatial distribution of cresset fields
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public20
OutlookCore scaffolds – exit vector distribution analysis
![Page 21: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/21.jpg)
Library design tool to distribute pharmacophoric constraints evenlyaround linking vector
Used to aid chemists visually select BBs from pharmacophoricclusters
Modified 2D descriptors should be used in conjunction
Applied in-house to large BB datasets for prioritization
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public21
Conclusions
![Page 22: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/22.jpg)
F. Berst
J. Ottl
C. Freslon
R. Martinez
P. Fille
A. Marzinzik
X. Pelle
Y. Ruff
S. Liverneau
S. Pickett
P. Lehr
M.-H. Bellance
V. Acker
P. Drueckes
K. Twesten
S. Haddad
C. Dumelin
M. Huebscher
J. Giovannoni
D. Ouzineb
N. Schneider
C. Gaul
P. Ertl
R. Lewis
H. Hemmerle
J. Duca
G. Landrum (now @ Knime)
P. Tosco
T. Cheeseright
M. Mackey
R. Chauhan
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public22
Acknowledgments
![Page 23: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/23.jpg)
BACKUPS
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public23
![Page 24: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/24.jpg)
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public24
Large discrepancies between AP and APRooted
![Page 25: Analyzing Building Blocks Diversity for DNA …...Cresset User Group Meeting Nik Stiefl & Finton Sirockin, Novartis 2016.06.16 Analyzing Building Blocks Diversity for DNA Encoded Library](https://reader034.vdocuments.mx/reader034/viewer/2022050512/5f9cf1d9c39d21787074559f/html5/thumbnails/25.jpg)
A DELibrary is not limited to a single central scaffold
| Cresset User Group Meeting 2016 | Nik Stiefl & Finton Sirockin | 2016.06 | Building blocks diversity for DELs | Public25
The Cauliflower™(Frédéric Berst)
It’s more like a trunk (scaffold) with cauliflowers fruits (capping) : a caulitree ?
Elements of design
Scaffold fragment set• Derivatization vectors• Pharmacophoric elements
Derivatisation fragment set• Pharmacophoric elements
HN
HN
N
HN