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.

Abstract: The present invention is directed to the use of computational and other experimental data in the design of new pharmaceuticals, and in predicting the metabolism and toxicological profiles thereof. Computational and other information is used to further understand drug metabolism and toxicology, particulary in relation to monooxygenase enzymes, such as those of the CYP system, that are involved in drug metabolism. Information derived according to the practice of the invention is useful in determining the clearance or half-life of drugs, and the nature and toxicity of byproducts resulting from their metabolism. The invention provides novel and powerful new approaches to drug design.

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.

Abstract: The present invention is directed to the use of computational and other experimental data in the design of new pharmaceuticals, and in predicting the metabolism and toxicological profiles thereof. Computational and other information is used to further understand drug metabolism and toxicology, particulary in relation to monooxygenase enzymes, such as those of the CYP system, that are involved in drug metabolism. Information derived according to the practice of the invention is useful in determining the clearance or half-life of drugs, and the nature and toxicity of byproducts resulting from their metabolism. The invention provides novel and powerful new approaches to drug design.

Abstract: Otherwise efficacious drugs having an ADMET/PK (absorption, distribution, metabolism, elimination, toxicity, i.e., pharmacokinetic) problem are redesigned or “rescued” by applying computational techniques that identify related chemical structures that preserve the initial drug's effectiveness but improve its ADMET/PK properties. The otherwise efficacious drug may be subjected to a suite of computational tools that identify sites responsible for problematic ADMET/PK properties and/or identify related compounds that have improved ADMET/PK properties.

Abstract: Systems and method are provided for modeling substrate molecules so that the various pathway reaction rates, and thus their overall reaction rates and metabolic properties, can be predicted. The current invention provides various systems and methods for stoichiometrically measuring the pathway reaction rates, both directly and indirectly. By repeating this for a class or several classes of substrate molecules, a general model of pathway reaction rates can be developed by correlating observed pathway reaction rates to the actual structural descriptors of the molecules, in particular, features around the reactive sites. The model can then be used to predict and design substrates according to desired metabolic characteristics. The systems and methods are particularly applicable to metabolism of substrate molecules by the cytochrome P450 enzymes.

Abstract: Accessibility correction factors may be used to modify values predicted by models of electronic component substrate reactivity. Most of the correction factors described herein pertain to either steric or orientation effects on substrate accessibility. The correction factors may be derived from one or more “descriptors” of the substrate structure. Each group of descriptors and associated correction factor pertain to a particular site on the substrate. Examples of such descriptors include site polarity, protrusion, partial surface area, partial charge, etc. Often the correction factor is a function of multiple descriptors. The function may be an expression comprising multiple terms, each representing the weighted contribution of a particular descriptor. In other embodiments, the correction factor is simply a descriptor or a descriptor multiplied by a coefficient or other function.

Abstract: Methods are disclosed for developing models used to rapidly predict metabolic stability and regioselectivity of drug molecules. Training sets, based on a sample of molecules with known reaction rates and/or activation energies, are used along with structural descriptors of the molecules in order to develop mathematical models of metabolism based on regression analysis of the activation energies and descriptors. The resulting models are then used to predict the metabolism of other molecules. The invention is particularly useful in developing simple models of cytochrome p450 enzyme metabolism.