ChemAxon. Content. By György Pirok. D Standardization D Virtual Reactions. D Fragmentation. ChemAxon European UGM Visegrad 2008

Transcription

1 Transformers f off ChemAxon By György Pirok Content Standardization Virtual Reactions Metabolism M b li P Prediction di i Fragmentation 2 1

2 Standardization 3 Introduction to Standardization Standardization is the first step of chemical canonicalization, the conversion of functional groups and other structural elements of molecules to a predefined representation. Standardizer is a tool for the standardization of structures, and it provides other conversion functions as well. Standardizer is available in the form of a integratable g class,, as a stand alone application, pp, and integrated with ChemAxon s databases as well. Standardizer is configurable by a list of actions to accommodate corporate standards. 4 2

3 Aromatizations Aromatize Basic Method Converts bonds to aromatic type according to the current resonant form of the molecule. 5 Aromatizations Aromatize General Method Converts bonds of rings having aromatic character to aromatic type. earomatize Converts aromatic bonds to alternating single/double bonds. 6 3

4 Hydrogen Actions Add Explicit Hydrogens Converts implicit hydrogens to explicit ones (adds hydrogen atoms to the graph). 7 Hydrogen Actions Remove Explicit Hydrogens Converts explicit hydrogens to implicit ones (removes hydrogen atoms from the graph). Special hydrogens (isotope, charged, radical, di l mapped, d lonely) l l ) can be b handled h dl d optionally. i ll 8 4

5 Stereo Actions Absolute Stereo Sets the chiral flag if a compound has tetrahedral stereo center. Clear Stereo Removes stereo features. 9 Stereo Actions Convert Wedge Interpretation Converts an wedge between two stereo centers into two separate wedges. Convert ouble Bonds Converts the crossed and wiggly representations of unknown stereo double bond 10 5

6 Clean Actions Clean2 Calculates the atom coordinates for two-dimensional structure representation. 11 Clean Actions Clean3 Calculates the lowest energy conformer of the molecule. 12 6

7 Clean Actions Wedge Clean Realigns wedge bond according to the IUPAC preferences. 13 Clean Actions Template based Cleaning Calculates the atom coordinates using templates. It is a useful action for the alignment of combichem libraries to the scaffold. 14 7

8 Group Actions Ungroup Ungroups superatoms and multiple groups irreversibly. Expand/Contract The superatoms and multiple groups can be opened and collapsed with these reversible actions (the group info remains in the structure). 15 Group Actions Alias to Group Converts alias and pseudo atoms to superatom groups according to their symbols. 16 8

9 Transform Actions Transform The transform action provides a general interface for user defined conversion of structural elements. Transforms are useful f the for h standardization d di i off mesomers, tautomers, salts l and d for f the h removal of specific counterions and solvents. 17 Salt Handling Actions Remove Fragment Provides various options to remove small fragments like counterions. 18 9

10 Salt Handling Actions Neutralize Neutralizes ionic functional groups but keeps the formal charges of mesomers and quaternary ammonium ions. 19 Reaction Mapping Actions Map Reactions Assignes map numbers to the corresponding atoms of a reaction scheme. Unmap Removes map numbers from the atoms of a reaction scheme

11 Other Actions Remove Isotopes Converts isotopic atoms to elemental atoms. 21 Standardizer emo 22 11

12 Future Plans Multiprocessor support Some complex actions will be converted to more smaller actions to improve readability of the configuration. Structure checker functionality (just check, report, but do not convert). New actions Group G ((autocreating i superatoms)) Convert to enhanced stereo Graphical design improvements. 23 Virtual Reactions

13 Reactor Reactor is an engine for the conversion of starting compounds to products according to a given reaction scheme Some applications are built on this engine, one is for combichem reaction processing. 25 A Classic Reaction Example 26 13

14 The Generic Reaction Scheme The hydrogen of an aromatic carbon atom is substituted with an acyl group of an acid halide during hydrogen halide elimination. C(a) L[O, S] L[Cl, Br, I] aromatic carbon atom oxygen or sulfur atom chlorine, bromine or iodine atom 27 Example Results 28 14

15 Exclude Sensitive Reactants Exclude acrylic halides and aromatic compounds containing nucleophilic groups. For example, phenols and indols can be processed, but benzylalcohols and anilines should not. REACTIVITY: match(reactant(1), "[Cl,Br,I]C(=[O,S])C=C") match(reactant(0), ( ( ) "[H][O,S]C=[O,S]")) match(reactant(0), "[P][H]") (max(pka(reactant(0), filter(reactant(0), "match('[o,s;h1]')"), "acidic")) > 14.5) (max(pka(reactant(0), filter(reactant(0), "match('[#7:1][h]', 1)"), "basic")) > 0) 29 Activation/eactivation The generic reaction is unselective, but additional rules improve the prediction. Friedel-Crafts acylation occurs only if the aromatic system is at least as activated as mono-halobenzenes. REACTIVITY: charge(ratom(1), "aromaticsystem") <

16 Regiospecifity The electrophilic substitution takes place on the aromatic carbon atom with the lowest localization energy having an attached electrophile in the transition state. Aromatic carbon with the lowest localization energy provides the main product product. Other aromatic carbons having similar localization energies (with less difference than 0.02) are also considered to lead to main products. SELECTIVITY: -energye(ratom(1)) TOLERANCE: Results with Rules 32 16

17 Reactor emo 33 Future Plans Multiprocessor and multicomputer support Reactant ratio All isomers in a single reaction output Multistep reactions (intermedier calculations) Reactant statistics (success rate for combichem) User interface simplifications (sketching in the wizard) Reaction library improvement of existing reactions new reactions Manual reaction site assignment Integration with Instant JChem 34 17

18 Metabolizm Prediction 35 Metabolizer Enumerates the metabolites of a given substrate Estimates metabolic stability Predicts major metabolites Human xenobiotic phase I. CYP450 biotransformation library is under development 36 18

19 Metabolic Stability Prediction S = max(v ) vmax max(v) is the speed category of the fastest consumption reaction of the given substrate (1: very slow, 2: slow, 3: medium, 4: fast, 5: very fast) vmax is the fastest speed category (5) In the example above, the metabolic stability of the substrate: S = 1 5/5 = 0 37 substrate The Metabolizm Model 38 19

20 The Major Metabolite Prediction Assumptions all metabolites are produced from a single original substrate the metabolic pathway of a substrate is known or predicted The speed of each metabolic transformation is known or predicted, and it is constant independently from the substrate or metabolite concentration the amount of the original substance is unknown, but it is not consumed completely various routes can lead to the same metabolite no cycles the effect of excretion can be included as a metabolic reaction 39 Key Indicators Transmissivity Speed ratio of the consumption and production reactions of a metabolite. Production The relative material flow to a metabolite. Accumulation Relative growth rate of a metabolite calculated from the transmissivity and production values. Metabolites with the highest accumulation rates are the major metabolites

21 Metabolizer 41 Biotransformation Speed The reaction speed estimation could be based on calculations from the given substrate It is applicable for very few reaction types only the similarity analysis of the same reaction with other substrates Measurements are available for few reaction types only and the published results are not consistent estimated for each reaction type Raw method that does not consider the substrate dependence, but it is trainable 42 21

22 Plans for the release and after Biotransformation library Test and review each reaction of the current library Refine reaction speed values manually, perhaps computationally Validate major metabolite prediction with published drug metabolism data Finish the design of the graphical user interface Provide a biotransformation library of reactive intermediates (useful for hepatotoxicity risk indication). 43 Fragmentation

23 The RECAP Method The RECAP method cleaves bonds of specific functional groups to create reusable building block for random evolutionary drug design and library analysis. RECAP - Retrosynthetic Combinatorial Analysis Procedure: A Powerful New Technique for Identifying Privileged Molecular Fragments with Useful Applications in Combinatorial Chemistry, J. Chem. Inf. Comput. Sci. 1998, c 45 RECAP onts o not open rings (it does not create smaller blocks) o not create too small fragments (too common) o not create fragments with too many connections (difficult to use) o not cleave bonds between hetero atoms and d aromatic ti rings i 46 23

24 Connection Labelling The connection points are labelled to store the type of the original functional groups. ether:1 amine:2 ether:2 amide:2 amide:1 amine:1 47 isadvantages of RECAP The fragments generated by the RECAP method are useful as building blocks for random evolutionary drug design, but not perfect for other purposes like toxicophore generation. Complex p configuration g The original publication contained 11 cleavage rules, the authors use more than 60 rules by now and some functional groups are still missing. Based on repetitive substructure search The identification of functional groups requires substructure search and well defined query structures. This can make the fragmentation unnecessarily time consuming Needs ring detection Some rules require q ring g detection which can be unnecessarily y time consuming. g Structural elements in aliphatic rings are not detected Since rings are not opened, important functionalities within aliphatic rings are not detected (like epoxides, for example). Requires labeling Functional groups are destroyed, so labeling is a must, so the fragments cannot be used directly as queries in database searching 48 24

25 The CCQ Fragmentation CCQ = Open the carbon-carbon single bonds next to a hetero atom in all permutations One simple O i l rule, l no configuration fi i fil file, reproducible d ibl Fast, no need for complex substructure searching Fast, no need for ring detection Breaks aliphatic rings, but does not break aromatics It leaves hetero atoms on aliphatic rings No need for labeling, it keeps the functional groups intact (a secondary amine remains secondary amine in the fragment) The fragments can be directly used as queries in database searching Avoids combinatorial explosion (does not fragment hydrocarbon chains) 49 CCQ Examples An exhaustive fragmentation of Erythromycin results combinatorial explosion, 250 possible fragments! 64k fragments g with CCQ in less than half minute. Rapid CCQ:8 fragmentation in less than 2 seconds results 4752 fragments (limiting the maximum CCQ groups to 8 in all permutations)

26 CCQ Examples An exhaustive fragmentation cleaving all bonds in all combinations of Erytromycin results combinatorial explosion, 250 possible fragments! An exhaustive CCQ fragmentation results 64k feasible fragments in less than half minute. 51 CCQ Examples 121 Hepatotoxic compounds can be fragmented by CCQ:8 fragmentation in less than a minute (133,332 fragments) 52 26

27 Thank you for your attention! tio For more information please visit 27