Abstract
Flavonoid compounds modulate the cytochrome P450 3A4 enzyme activity and inhibit the mutagenic activity of mammalian cells, preventing carcinogen activation and cellular DNA damage. In this work, the quantitative structure-activity relationships (QSAR) theory is applied to predict the cytochrome P450 3A4 inhibition constant by anthocyanin derivatives. Different freely available software calculates 102,260 non-conformational molecular descriptors. A training set of 12 compounds is used to calibrate the best univariable linear regression models, while a test set of 4 compounds is used to explore their predictive capability. The present results are compared with previously reported ones by using 3D-QSAR, thus demonstrating that the proposed topological QSAR models achieve acceptable statistical quality. The proposed model provides a prospective QSAR guide for the search of new anthocyanin derivatives possessing high or low predicted mutagenicity.
Highlights
The family of cytochrome P450 (CYP) proteins is widely distributed in all kingdoms of life, from bacteria, archaea, and viruses to higher plants and animals
The substrates of CYP proteins can be very varied, including endogenous compounds produced by cell metabolism, and exogenous substances such as biogenic amines (Sánchez-Jiménez et al, 2013), cytostatic agents (Evteev et al, 2006), and steroids (Yamazaki et al, 1998)
From the pool of 47,117 linearly independent descriptors, different single variable linear regression models are first identified, by searching for the smallest values of the root mean square (RMS ) error parameter in the training set. After this initial optimization step, different model evaluation criteria are considered for selecting the best linear model, such as the root mean square error (RMS) value in the test set, cross-validation results, number of outlier compounds, and other theoretical validation strategies
Summary
The family of cytochrome P450 (CYP) proteins is widely distributed in all kingdoms of life, from bacteria, archaea, and viruses to higher plants and animals. The substrates of CYP proteins can be very varied, including endogenous compounds produced by cell metabolism, and exogenous substances such as biogenic amines (Sánchez-Jiménez et al, 2013), cytostatic agents (Evteev et al, 2006), and steroids (Yamazaki et al, 1998). CYPs are monooxygenases that contain a heme group, which catalize a variety of reactions, such as hydroxylation, epoxidation, oxidation, reduction, deamination, dehalogenation, dealkylation, dehydrogenation, and demethoxygenation (Ortiz de Montellano&De Voss, 2005; Gillam&Hunter, 2007). CYP3A4 is the most abundant human isoform. CYP3A4 is found in the liver and it metabolizes, completely or partially, around 45-60% of clinical drugs (Li et al, 2018).
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