Modeling of cytochrome P-450 enzyme inhibitors activities using 2D/3D QSAR
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Modeling of cytochrome P‑450 enzyme inhibitors activities using 2D/3D QSAR Farahmand Asadi1 · Mohammad Hossein Fatemi1 Received: 13 April 2020 / Accepted: 10 August 2020 © Springer Nature Switzerland AG 2020
Abstract In this research, quantitative structure–activity relationship (QSAR) studies were carried out on the inhibitory activities of a set of nicotine derivatives against the cytochrome-p450 2A6 (CYP2A6) enzyme. Two-dimensional quantitative structure–activity relationship (2D-QSAR) models were developed using multiple linear regression (MLR) and linear square-support vector machine (LS-SVM) methods. The result of statistical parameters of the MLR method show that the correlation coefficient (R2) and standard error (SE) for the training set respectively are R2 = 0.702, SE = 0.49 and for the test set R2 = 0.689, SE = 0.52 and the results of statistical parameters of the LS-SVM method for the training set R2 = 0.993, SE = 0.10 and for the test set R 2 = 0.977, SE = 0.20. The obtained results reveal the superiority of LS-SVM over MLR model. Then three-dimensional quantitative structure–activity relationship (3D-QSAR) model was developed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) on the same dataset of nicotine derivatives. The acquired statistical parameters of the CoMFA model for the training set are R 2 = 0.884, SE = 0.316 2 2 and for the test set R = 0.847, SE = 0.33, F = 41.27, Q = 0.581, while the statistical values of CoMSIA model for the training set are R2 = 0.889, SE = 0.31 and for the test set R2 = 0.670, SE = 0.54, F = 39.049, Q2 = 0.554. The results of this study revealed that the CoMFA model was more predictive and could be helpful in designing novel potent nicotine derivatives with enhanced inhibitory activity. Keywords CoMFA · CoMSIA · Cytochrome P-450 2A6 · Inhibitory activity · LS-SVM · MLR
1 Introduction Tobacco contains a package of harmful and addictive compounds [2] that its all forms rise the health problems in humans [47]. Long-term is speaking of lung cancer, heart disease, stroke and other fatal and non-fatal diseases [7, 23, 33]. Tobacco is the common cause of premature death compared to other consumer products [37]. It kills more people in developing countries than in industrialized countries [18]. The principal ingredient of tobacco leaves is nicotine which is highly addictive [3]. Even though numerous smoking-related diseases are preventable but due to the dependency of a smoker to nicotine, only a small
number of smokers manage to quit perfectly. Researchers have developed different nicotine replacements like nicotine gum and patch, to lower the addiction liability and to assist in smoking cessation [44]. The metabolism of nicotine leads to several metabolites [26]. In humans, the major product of this conversion is cotinine [4]. Hepatic Cytochrome P-450 2A6 (CYP2A6) is widely considered to be the principal catalyzing enzymes of nicotine metabolism via the intermediacy of aldehydes-catalyzed
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