Method for predicting activation energy using an atomic fingerprint descriptor or an atomic descriptor

Abstract

The present invention provides a method for constructing a database of atomic fingerprint descriptors. The invention provides a method for predicting activation energy using an atomic fingerprint descriptor and an atomic descriptor, the method comprising the steps of: (i) calculating the atomic fingerprint descriptor of a substrate; (ii) comparing the calculated atomic fingerprint descriptor with the constructed atomic fingerprint descriptor database to select an atomic position where cytochrome P450-mediated metabolism occurs; and (iii) predicting activation energy for the selected atomic position using an atomic descriptor. Also, the invention provides a method of predicting the activation energy of CYP450-mediated phase I metabolism using effective atomic descriptors. Specifically, the invention provides a method of predicting the activation energy either for cytochrome P450-mediated hydrogen abstraction or for tetrahedral intermediate formation in cytochrome P450-aromatic hydroxylation using equations including effective atomic descriptors. The method of the invention can rapidly predict activation energy for phase I metabolites at a practical level without having to perform a docking experiment between any additional CYP450 and the substrate, or a quantum mechanical calculation, thereby making it easier to develop new drugs using a computer. Also, the present invention may propose a strategy for increasing the bioavailability of drugs through the avoidance of metabolites based on the possibility of drug metabolism. Furthermore, the method of the present invention proposes new empirical approaches which can also be easily applied to activation energies for various chemical reactions, and makes it possible to explain physical and chemical factors that determine activation energy. In addition, through the prediction of activation energy according to the present invention, it is possible to predict i) metabolic products, ii) the relative rate of metabolism, iii) metabolic regioselectivity, iv) metabolic inhibition, v) drug-drug interactions, and vi) the toxicity of a metabolite.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The present invention relates to a method for predicting the activation energy of phase I metabolism, mediated by CYP450 enzymes, using an effective atomic fingerprint descriptor or atomic descriptor.[0003]2. Description of the Prior Art[0004]The prediction of absorption, distribution, metabolism and excretion (ADME) properties of drugs is a very important technique to shorten the drug development period and to enhance the probability of success of drug development. Among the drug's ADME properties, drug metabolism is a key determinant of metabolic stability, drug-drug interactions, and drug toxicity.[0005]Metabolic reactions can be divided according to the reaction mechanism into two categories: aliphatic hydroxylation and aromatic hydroxylation. Also, they can be divided according to the type of reaction into the following categories: N-dealkylation, C-hydroxylation, N-oxidation, O-dealkylation and the like. In alipha...

AI Technical Summary

Benefits of technology

[0038]The present invention provides a method of predicting a metabolite of a CYP450 enzyme by predicting binding possibility using an atomic-type fingerprint descriptor, which includes the type of atom and the surrounding bond order, and by predicting reactivity using an atomic descriptor. The method of the present invention solves a time-consuming problem in predicting accessibility using the three-dimensional structure of a CYP450 enzyme and does not require any quantum mechanical calculation or experiment.

[0044]To achieve another object, the present invention provides a method of predicting the activation energy for CYP450-mediated hydrogen abstraction according to an equation including an effective atomic descriptor. This method of the present invention is fast and accurate and does not require any quantum mechanical calculation or experiment.

[0051]To achieve another object, the present invention provides a method of predicting the activation energy for CYP450-mediated aromatic hydroxylation according to an equation including an effective atomic descriptor. The method of the present invention is fast and accurate and does not require any quantum mechanical calculation or experiment.

Problems solved by technology

Such reaction rate and regioselectivity can be predicted from activation energy, but existing methods depend on time-consuming quantum mechanical calculations and difficult experiments.

However, such quantum mechanical methods perform calculations in various molecular states, and thus cannot determine accurate activation energy due to the complexity resulting from the conformational difference between these states.

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