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• http://ich.vscht.cz/~svozil/teaching.html
EXPLORING CHEMICAL SPACE FOR DRUG DISCOVERYDaniel Svozil [email protected]
Laboratory of Informatics and Chemistry
University of Chemistry and Technology Prague
What is chemical space?
size: 3 × 1023 stars, 1080 atoms Dokkum & Conroy, Nature, 2010, 468, 940–942
http://www.universetoday.com/21528/sweet-galactic-molecule-could-point-to-alien-life/
Size of chemical space• mono- to 14-substitute n-hexanes … 1029
Weininger, In Encyclopedia of Computational Chemistry, 1998, Vol. 1, 425-530
• estimates vary wildly, commonly given … 1060 (MW<500, stable, not all synthetically available)Bohacek et al., Med. Res. Rev., 1996, 16, 3-50
• CAS … 1.0 × 108
• ZINC … 2.3 × 107
• DrugBank … 7 759 drugs
all numbers as of 1. 9. 2015
Why we need to explore chemical space
Lipinski & Hopkins, Nature. 2004, 432, 855-61
chemical space
gene family
administered drugs
Methods of its exploration• experimental
• synthesis – combinatorial chemistry• related biological data – high-throughput screening (HTS)
• computational
http://www.cam-com.com/images/comchem.jpghttp://chemgen.cz/
Computational exploration of chemical space
This is basically de novo design. It means that new chemotypes with desired effects are proposed.
Two major approaches
1. Exhaustive enumeration
2. Molecular evolution
Once you have a virtual library generated, you can apply any of possible virtual screening methods to prioritize your compounds.
Exhaustive enumeration• prof. Reymond, Bern• GDB databases, all molecules that can exist up to a
certain number of heavy atoms• GDB-11 ( compounds with C, N, O, F)• GDB-13 ( compounds with C, N, O, S, Cl)• GDB-17 ( compounds with C, N, O, S, halogens)
Molecular evolution• systematicaly explore chemical space by clever generation of new
compounds
Kawai et al., J. Chem. Inf. Model. 2014, 54, 49-56.
Virtual screening ‘funnel’
~106 – 109
molecules
VIRTUAL SCREENING
INACTIVES
HITS
GENERATED DATABASE (Q)SAR
Docking
Pharmacophore models
~101 – 103
molecules
From the presentation by A. Varnek, University of Strasbourg
Filters
Molpher• Molecular morphing
Svozil et al., J. Cheminform., 2014 , 6, 7.
Morphing between two molecules
Svozil et al., J. Cheminform., 2014 , 6, 7.
Morphing operators
Svozil et al., J. Cheminform., 2014 , 6, 7.
Molpher – what is it good for?• Idea: start and target molecules are active against the
same target• In a systematic way, generate chemical subspace
between a start/target pair• Explore this subspace for molecules with high potency
IMG library
ChEMBL
GR ligands
Data cleaning and consolidation Molpher
Pool of posible ligands
ZINC
Purchase compounds
Experimental verification
297 GR ligands87 912 paths
~ 2 000 000 morphs
ACKNOWLEDGMENTLICH group: Ctibor Škuta, Milan Voršilák, Ivan Čmelo,
Martin Šícho, Jiří Novotný
IMG group of chemical biology: Petr Bartůněk, David Sedlák and others