Chemical Biology Chemical versus Biological Space & Chemical Genomics A growing interest in using chemicals as probes/detectors in basic and clinical research Nowadays, Study of Biological processes biological components the study of biological unction of modulating function of biological components modulating f Small Molecule Mutation

Chemical Genetics Chemical Genetics: processes using small molecule intervention (rather than genetic intervention) Genetics Chemical Genetics Genome-Wide is the extension of Chemical Genomics Chemical Genetics to a Scale Chemical Genetics and Chemical Genomics nomics e The goal of Chemical Genomics is to map the "biological activity space" in the "chemical space" using small molecules Chemical G Forward and Reverse Chemical Genomics Reverse Forward (target based screen) (phenotype based screen)

Target (e.g. protein) Phenotype

Small Small Molecules Molecules Interacting Causing with target Phenotype Phenotype Target (e.g. protein) Commonly More recent used Small Forward Cells molecules Chemical (Libraries)

Genetics Assay and "hit" Wanted identification Phenotype Confirmation- From a dilution series phenotype to Optimization by the target testing analogs

Confirmation of desired phenotype in model organisms Optimizing for a Identification of drug (e.g. toxicity target small tests and clinical molecule testing small mechanisms biological systems and and iscovery and elucidation of ystematic exploration of the D S - novel targets of action - interactions between molecules The Field of Chemical Genomics ich collections of small molecules will xamines known, biologically active R Chemical Genomics E - small molecules but requires novel collections of small molecules with large diversity - increase the chance of discovering biologically active molecules for basic and applied (e.g. drugs) research 60 hemical compounds populating space instead nalogous to the cosmological universe in its stimated number of small carbon-based The Chemical Space C E A - size/extent - of stars - compounds (up to 500 Da) is more than 10 ) than there are 29

The Chemical Space Theoretical chemists have calculated that there are more possible molecules based on hexane (10 stars in the visible universe The Chemical Space

-- ChemistsChemists mademade aa minorminor amountamount ofof visitsvisits intointo thisthis (chemical)(chemical) spacespace -- LargestLargest chemicalchemical databasesdatabases currentlycurrently containcontain upup toto 2525 millionmillion differentdifferent moleculesmolecules mapped in the chemical … by multiple "descriptors" that

The Chemical Space Chemicals can be space describe their structure, activities and properties Examples of descriptors are: molecular mass, lipophilicity, geometric properties and many more defined by calculations and observation of the effect : d e v r e s b omputed: wo fundamentally different classes of T C - descriptors used to map chemicals in the chemical space - algorithms -O The Chemical Space chemical on for example genes, proteins PCA models of a chemical space for 480 small molecules 24 computed molecular descriptors 60 measured phenotypic descriptors derived from a cell- based assay

Creating Maps of Chemical Space iological systems use a tiny portion of The Biologically Relevant Chemical Space iving systems contain from hundreds to B L - the possible amount of compounds possible in the same range of molecular masses - thousands of compounds The Biologically Relevant Chemical Space Thus, in terms of numbers, "biologically relevant chemical space" is only a tiny fraction of the "chemical space" The limits of the biologically relevant chemical space is defined by the interaction between the small molecules and the biological molecules such as DNA, RNA and proteins as h y Gene Famil Administared drugs Chemical space s" (proteins from the same family suc in specific regions of the chemical space y

The Biologically Relevant Chemical Space Famil Gene Compounds that bind to certain "target classe G-protein-coupled receptors, cluster together Evolution WHY? during the evolution of living systems, limited range of chemical reactions exploited

The Biologically Relevant Chemical Space & o many complex processes in a cell could be S -A - carried out with a limited number of molecules!! Evolution etal ions and co-factors incorporated into folded ssential chemistry for life (atoms and other ide chains of proteins (methyl group, isopropyl, thiol The Biologically Relevant Chemical Space & 9% of the atoms within a biological system are C, H, M E 9 S - - elements/groups): - O or N - and others), approximately 20 of them structures The Biologically Relevant Chemical Space & Evolution Solubility in water is a key issue: -Many of thesmall organic molecules used by biological systems are derivatives of carboxylic acids and organic amines (charged, hydrophilic at physiological pH)

- Amino acid side chains are in part very hydrophobic and others are hydrophilic and this allows folding (at low energy cost) Evolution any small molecules in living organisms are hsophoric acid derivatives, phospholipids are The Biologically Relevant Chemical Space & TP is the energy store in biology and M P A Another key issue is the production of ATP: - building block for DNA and RNA - derivatives of phosphoric acid, the precursor for ATP formation - key components of biological membranes he biological space is mapped by using the small iological systems are classified instead of chemicals

The Biological Space T B - molecules as descriptors - he biological space is mapped by using the he biological space will classify T T

The Biological Space - systems instead of chemicals - small molecules as descriptors chemical and he biological space will classify he biological space is mapped by using the he analysis of multi-dimensional data (with T T T - systems instead of chemicals - small molecules as descriptors The Biological Space - dimensiobility reduction and pattern finding methods) provides a computational framework for mapping multidimensional biological descriptor spaces Next Week Next Week Navigating the Chemical Space for Biology and Medicine Tools and Examples