Patent
أعرض في EDS

SYSTEM AND METHOD TO IDENTIFY THE METABOLITES OF A DRUG

التفاصيل البيبلوغرافية
العنوان: SYSTEM AND METHOD TO IDENTIFY THE METABOLITES OF A DRUG
Document Number: 20080120041
تاريخ النشر: May 22, 2008
Appl. No: 11/938418
Application Filed: November 12, 2007
مستخلص: The invention provides for a method for predicting potential metabolites for a compound, comprising the steps of receiving a target compound from a user applying a set of optimized reaction rules to said target compound to generate a list of potential metabolites and calculating a probability score for each product compound on said list of potential metabolites. The reaction set is optimized by starting from a starting set of reaction rules and replacing at least one reaction rule for a reaction center in said starting set of reaction rules by one, or preferably two or more new rules, which are defined to apply to a reaction of said reaction center, but now specifying or differentiating based on the structural environments of said reaction center, if at least one of said new rules has a higher probability score than the replaced reaction rule when the starting set of reaction rules and the optimized set of reaction rules are both tested with a database of known metabolites of compounds.
Inventors: Ridder, Lars-Olaf (Oss, NL); Wagener, Markus (Oss, NL); Lommerse, Johannes Petrus Maria (Oss, NL)
Assignees: N.V. Organon (Oss, NL)
Claim: 1. A system for predicting potential metabolites for a compound, comprising: a user input device to allow a user to indicate a target compound to be analyzed for potential metabolites; a data processor capable of applying a set of optimized reaction rules to said target compound to generate a list of potential metabolites and calculate a probability score for each potential metabolite; means to make the resulting list of potential metabolites available to the user or to a further processing instrument.
Claim: 2. The system according to claim 1, wherein said data processor comprises a filter that is capable of eliminating from said list of potential metabolites those metabolites having a calculated probability score that falls below a certain limit.
Claim: 3. The system according to claim 1, wherein the set of reaction rules has one or more of the characteristics selected from the list consisting of: a) the presence of 16 different rules for N-dealkylation; b) the presence of separate rules for N-dealkylation of amines either connected to aromatic carbons or to aliphatic groups only; c) the presence of different rules for hydroxylation of aliphatic carbons, one of those for a tertiary carbon, which should be attached to an sp2 hybridised atom and one of those for a secondary carbon in a ring attached to sp2 hybridised atoms on both sides; d) the presence of a rule for ring-forming condensation reactions; e) the presence of a rule for beta-oxidation of aliphatic carboxylic acids f) the presence of a rule for glycination g) the presence of a rule for phosphorylation h) the presence of rules for specific reactions applicable to steroids; i) the presence of rules for dehydrogenations which result in extension of a conjugated system in a molecule.
Claim: 4. The system according to claim 1, wherein the set of reaction rules comprises a set of at least 10 different rules for hydroxylation, and with those rules at least two or more distinctions in hydroxylations are made selected for the list consisting of: a) a distinction in aromatic, aliphatic and benzylic hydroxylation; b) a distinction in aromatic hydroxylation of 5- and 6-membered aromatic rings; c) a distinction in aromatic hydroxylation of aromatic carbon atoms positioned para, meta or ortho to non-hydrogen substituents; d) a distinction in aromatic hydroxylation between aromatic carbon atoms positioned meta to non-hydrogen substituents and said aromatic carbon atoms being at the same time 1) either positioned ortho or para to another non-hydrogen substituent or 2) positioned ortho or para to a hydrogen atom; e) a distinction in aromatic hydroxylation between aromatic carbons atoms positioned ortho to non-hydrogen substituents and said aromatic carbon atoms being at the same time a) either positioned meta or para to another non-hydrogen substituent or b) positioned meta or para to a hydrogen atom; f) a distinction in aromatic hydroxylation of substituents connected to the aromatic system via a carbon, oxygen, nitrogen or any non-hydrogen atom; g) a distinction in aromatic hydroxylation of nitrogen and sulfur containing 5-membered aromatic rings; h) a distinction in hydroxylation of primary, secondary or tertiary aliphatic carbon atoms; i) a distinction in hydroxylation of aliphatic carbon atoms connected to heteroatoms or carbon atoms; j) a distinction in hydroxylation of aliphatic carbon atoms connected to aromatic carbon atoms, conjugated non-aromatic atoms, or aliphatic carbon atoms; k) a distinction in hydroxylation of aliphatic carbon atoms connected to methyl groups or secondary, tertiary or quaternary carbon atoms; l) a distinction in hydroxylation of aliphatic carbon atoms connected to atoms which are connected to methyl groups, heteroatoms, conjugated carbon atoms or aromatic carbon atoms; m) a distinction in hydroxylation of aliphatic carbon atoms which are part of a ring and those which are not part of a ring.
Claim: 5. The system according to claim 1, wherein the set of reaction rules comprises at least 10 rules for hydroxylation and at least one of those rules is selected from the list consisting of: a) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned para to another carbon; b) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned para to a nitrogen; c) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned para to an oxygen; d) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned meta to a carbon and not positioned para to a non-hydrogen atom; e) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned ortho to a carbon and not positioned para and/or ortho to a non-hydrogen atom; f) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned ortho to a nitrogen and not positioned para to a non-hydrogen atom; g) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned ortho to an oxygen and not positioned para to a non-hydrogen atom; h) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned ortho to two non-hydrogen substituents, one of which needs to be carbon, oxygen or nitrogen; i) a rule for hydroxylation of an aromatic carbon atom in 5-membered ring connected to a sulfur in said ring; j) a rule for hydroxylation of an aromatic carbon atom in 5-membered ring connected to a nitrogen in said ring; k) a rule for hydroxylation of a primary aliphatic carbon connected to a quaternary carbon which is connected to at least one heteroatom; l) a rule for hydroxylation of a primary aliphatic carbon connected to a tertiary carbon which is connected to at least methyl group; m) a rule for hydroxylation of a primary aliphatic carbon connected to a secondary carbon; n) a rule for hydroxylation of a primary aliphatic carbon connected to a carbon which is connected by either a double or a triple bond to yet another atom; o) a rule for hydroxylation of a secondary aliphatic carbon connected to a methyl group and another tetravalent carbon; p) a rule for hydroxylation of a secondary aliphatic ring carbon connected to two secondary carbons; q) a rule for hydroxylation of a secondary aliphatic ring carbon connected to a secondary carbon and another tetravalent non-secondary carbon which is connected to either a methyl group or a heteroatom; r) a rule for hydroxylation of a secondary aliphatic non-ring, non-benzylic carbon connected to a tetravalent carbon and another atom which is connected by a double bond to yet another atom; s) a rule for hydroxylation of a secondary aliphatic non-benzylic ring carbon connected to a tetravalent carbon and another atom which is either a nitrogen or connected by a double bond to yet another atom; t) a rule for hydroxylation of a secondary aliphatic non-benzylic ring carbon connected to two atoms which are connected by a double bond to yet another atom; u) a rule for hydroxylation of a tertiary carbon connected to two aliphatic carbons, one of which is connected to either a nitrogen atom or a carbon atom connected by a double bond to yet another atom; v) a rule for hydroxylation of a non-benzylic tertiary carbon connected to two methyl groups; w) a rule for hydroxylation of a benzylic methyl group.
Claim: 6. A method for predicting potential metabolites for a compound, comprising the steps of: receiving a target compound; applying a set of optimized reaction rules to said target compound to generate a list of potential metabolites; calculating a probability score for each potential metabolite on said list of potential metabolites.
Claim: 7. The method according to claim 6, wherein the set of reaction rules has one or more of the characteristics selected from the list consisting of: a) the presence of 16 different rules for N-dealkylation; b) the presence of separate rules for N-dealkylation of amines either connected to aromatic carbons or to aliphatic groups only; c) the presence of different rules for hydroxylation of aliphatic carbons, one of those for a tertiary carbon, which should be attached to an sp2 hybridised atom and one of those for a secondary carbon in a ring attached to sp2 hybridised atoms on both sides; d) the presence of a rule for ring-forming condensation reactions; e) the presence of a rule for beta-oxidation of aliphatic carboxylic acids f) the presence of a rule for glycination g) the presence of a rule for phosphorylation h) the presence of rules for specific reactions applicable to steroids; i) the presence of rules for dehydrogenations which result in extension of a conjugated system in a molecule.
Claim: 8. The method according to claim 6, wherein the set of reaction rules comprises a set of at least 10 different rules for hydroxylation, and with those rules at least two or more distinctions in hydroxylations are made selected for the list consisting of: a) a distinction in aromatic, aliphatic and benzylic hydroxylation; b) a distinction in aromatic hydroxylation of 5- and 6-membered aromatic rings; c) a distinction in aromatic hydroxylation of aromatic carbon atoms positioned para, meta or ortho to non-hydrogen substituents; d) a distinction in aromatic hydroxylation between aromatic carbon atoms positioned meta to non-hydrogen substituents and said aromatic carbon atoms being at the same time 1) either positioned ortho or para to another non-hydrogen substituent or 2) positioned ortho or para to a hydrogen atom; e) a distinction in aromatic hydroxylation between aromatic carbons atoms positioned ortho to non-hydrogen substituents and said aromatic carbon atoms being at the same time a) either positioned meta or para to another non-hydrogen substituent or b) positioned meta or para to a hydrogen atom; f) a distinction in aromatic hydroxylation of substituents connected to the aromatic system via a carbon, oxygen, nitrogen or any non-hydrogen atom; g) a distinction in aromatic hydroxylation of nitrogen and sulfur containing 5-membered aromatic rings; h) a distinction in hydroxylation of primary, secondary or tertiary aliphatic carbon atoms; i) a distinction in hydroxylation of aliphatic carbon atoms connected to heteroatoms or carbon atoms; j) a distinction in hydroxylation of aliphatic carbon atoms connected to aromatic carbon atoms, conjugated non-aromatic atoms, or aliphatic carbon atoms; k) a distinction in hydroxylation of aliphatic carbon atoms connected to methyl groups or secondary, tertiary or quaternary carbon atoms; l) a distinction in hydroxylation of aliphatic carbon atoms connected to atoms which are connected to methyl groups, heteroatoms, conjugated carbon atoms or aromatic carbon atoms; m) a distinction in hydroxylation of aliphatic carbon atoms which are part of a ring and those which are not part of a ring.
Claim: 9. The method according to claim 6, wherein the set of reaction rules comprises at least 10 rules for hydroxylation and at least one of those rules is selected from the list consisting of: a) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned para to another carbon; b) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned para to a nitrogen; c) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned para to an oxygen; d) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned meta to a carbon and not positioned para to a non-hydrogen atom; e) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned ortho to a carbon and not positioned para and/or ortho to a non-hydrogen atom; f) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned ortho to a nitrogen and not positioned para to a non-hydrogen atom; g) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned ortho to an oxygen and not positioned para to a non-hydrogen atom; h) a rule for hydroxylation of an aromatic carbon in a 6-membered ring positioned ortho to two non-hydrogen substituents, one of which needs to be carbon, oxygen or nitrogen; i) a rule for hydroxylation of an aromatic carbon atom in 5-membered ring connected to a sulfur in said ring; j) a rule for hydroxylation of an aromatic carbon atom in 5-membered ring connected to a nitrogen in said ring; k) a rule for hydroxylation of a primary aliphatic carbon connected to a quaternary carbon which is connected to at least one heteroatom; l) a rule for hydroxylation of a primary aliphatic carbon connected to a tertiary carbon which is connected to at least methyl group; m) a rule for hydroxylation of a primary aliphatic carbon connected to a secondary carbon; n) a rule for hydroxylation of a primary aliphatic carbon connected to a carbon which is connected by either a double or a triple bond to yet another atom; o) a rule for hydroxylation of a secondary aliphatic carbon connected to a methyl group and another tetravalent carbon; p) a rule for hydroxylation of a secondary aliphatic ring carbon connected to two secondary carbons; q) a rule for hydroxylation of a secondary aliphatic ring carbon connected to a secondary carbon and another tetravalent non-secondary carbon which is connected to either a methyl group or a heteroatom; r) a rule for hydroxylation of a secondary aliphatic non-ring, non-benzylic carbon connected to a tetravalent carbon and another atom which is connected by a double bond to yet another atom; s) a rule for hydroxylation of a secondary aliphatic non-benzylic ring carbon connected to a tetravalent carbon and another atom which is either a nitrogen or connected by a double bond to yet another atom; t) a rule for hydroxylation of a secondary aliphatic non-benzylic ring carbon connected to two atoms which are connected by a double bond to yet another atom; u) a rule for hydroxylation of a tertiary carbon connected to two aliphatic carbons, one of which is connected to either a nitrogen atom or a carbon atom connected by a double bond to yet another atom; v) a rule for hydroxylation of a non-benzylic tertiary carbon connected to two methyl groups; w) a rule for hydroxylation of a benzylic methyl group.
Claim: 10. A method to identify the metabolites of a drug in a mammalian body by entering the structural formula of the drug into a computer program, which computer program provides the structural formulas of possible metabolites by screening for possible metabolic transformations and the probabilities thereof for the drug by using a list of possible metabolic transformations and the corresponding probabilities of those transformations, characterized in that the list contains subsets of metabolic transformation depending on the position of the modified part of the drug in the structure of the drug.
Claim: 11. The method according to claim 10, wherein the method is implemented in a computer connected to a mass spectrometer for adjustment of the mass identification mechanism of fragments.
Claim: 12. A method of making an optimized set of reaction rules from a starting set of reaction rules for use in the system according to claim 1, which method of making an optimized set of reaction rules comprises the step of replacing at least one reaction rule for a reaction center in said starting set of reaction rules by one or more new rules, which are defined to apply to a reaction of said reaction center, but now specifying or differentiating based on the structural environments of said reaction center, if at least one of said new rules has a higher probability score than the replaced reaction rule when the starting set of reaction rules and the optimized set of reaction rules are both tested with a database of known metabolites of compounds.
Current U.S. Class: 702/19
Current International Class: 06
رقم الانضمام: edspap.20080120041
قاعدة البيانات: USPTO Patent Applications
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