Relative rates of cytochrome p450 metabolism
AssigneesWashington State University Research Foundation, ArQule, Inc.
InventorsKenneth R. Korzekwa, Jeffrey P. Jones
Life of this patent
Estimating the term…
Abstract
Reactive sites on a substrate molecule, typically a drug, may be identified and the relative rates of their metabolism by the CYP enzymes may be determined. Determining these relative rates is an important factor in determining the absolute rate of metabolism of the individual sites and the substrate molecule as a whole. This information is also a critical factor in determining whether and how the substrate can be redesigned to improve its ADME/PK properties. In this regard, it is particularly important to know how the relative rates compare to the rate of a non-metabolic side reaction (branch pathway) such as water generation and regeneration of the substrate.
Claims25
A computer-implemented method of characterizing a reactive site of a substrate molecule, the method comprising the operations of:
- a) determining a first activation energy or a first rate constant of a main reaction pathway at the reactive site of the substrate, while the substrate is complexed with an enzyme, to produce a product molecule;
- and
- b) comparing the first activation energy or the first rate constant of the main reaction pathway at the reactive site to a value of a second activation energy or a second rate constant of a branch decoupling reaction pathway of the substrate molecule in complex with the enzyme, which comparison facilitates a decision of whether or how to reengineer the substrate molecule.
A computer system capable of characterizing a reactive site of a substrate molecule by comparing a reaction at the reactive site, resulting in generation of a product molecule, to a branch decoupling reaction of the substrate molecule in complex with an enzyme, the computer system comprising:
- one or more processors;
- one or more user input devices;
- and
- memory;
- wherein the processor and memory are configured to
- a) determine a first activation energy or a first rate constant of a main reaction pathway at the reactive site of the substrate molecule, while the substrate is complexed with the enzyme, to produce the product molecule;
- and
- b) compare the first activation energy or the first rate constant of the main reaction pathway at the reactive site to a value of a second activation energy or a second rate constant of a branch decoupling reaction pathway of the substrate molecule in complex with the enzyme.
A computer-program product comprising a computer-readable medium and program instructions provided via the computer-readable medium, the program instructions comprising instructions for characterizing a reactive site of a substrate molecule by comparing a reaction at the reactive site, resulting in generation of a product molecule, to a branch decoupling reaction of the substrate molecule in complex with an enzyme, the instructions specifying:
- a) determining a first activation energy or a first rate constant of a main reaction pathway at the reactive site of the substrate molecule, while the substrate is complexed with the enzyme, to produce the product molecule;
- and
- b) comparing the first activation energy or the first rate constant of the main reaction pathway at the reactive site to a value of a second activation energy or a second rate constant of a branch decoupling reaction pathway of the substrate molecule in complex with the enzyme.
Dependencies are inferred from the claim text.