Molecular docking, linear and nonlinear QSAR studies on factor Xa inhibitors
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ORIGINAL RESEARCH
Molecular docking, linear and nonlinear QSAR studies on factor Xa inhibitors Monireh Ramandi 1 & Siavash Riahi 2 & Hamzeh Rahimi 3 & Mohammad Mohammadi-Khanaposhtani 1 Received: 10 December 2019 / Accepted: 13 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Factor Xa (FXa) enzyme has an important role in the blood coagulation system. Disruption in the enzyme function results in the production of blood clots. Therefore, inhibition of the factor Xa with anticoagulant drugs is an important target in thromboembolic therapy. Experimental design of new drugs is a time-consuming and expensive process. Application of molecular modeling is an essential step for designing new and high yield drugs to achieve better results. In this study, 36 aroylguanidine derivatives that inhibit destructive activities by binding to the FXa enzyme were selected. Quantitative Structure-Activity Relationships (QSAR) model was developed for predicting the IC50 parameter for factor Xa inhibitors. QSAR have been constructed by combining Genetic Algorithms with Multiple Linear Regressions (GA-MLR) and Support Vector Machine (SVM). The correlation coefficient (R2) and root mean square error (RMSE) for GA-MLR are 0.895, 0.142 and for SVM are 0.994, 0.032, respectively. The obtained results indicated that the SVM method is superior over the GA-MLR method. Also, molecular docking was used to examine the results more accurately, in which energy interactions were investigated. Molecular docking indicated the binding relationship between the receptor and the ligand. The results showed that reducing the parameters such as electronegativity, and the size of the atoms, as well as increasing the number of loops and groups attached to the structures, is effective in the model. Keywords Factor Xa . Molecular docking . Quantitative structure-activity relationships . Blood coagulation . Drug design
Introduction The factor Xa is a serine protease, is synthesized in the liver, and plays an important role in the blood coagulation system [1, 2]. It is a molecular target and it is used to develop anticoagulant drugs for the thromboembolic disorders treatment which leads to morbidity and mortality worldwide [3]. Therefore, factor Xa inhibition is an efficient strategy to treat thromboembolic diseases [4]. The anticoagulant drugs such as warfarin and the heparin series are commonly used to inhibit the factor Xa activities [5]. New drugs design is very expensive and time consuming. Thus, the * Siavash Riahi [email protected] 1
Faculty of Fouman, College of Engineering, University of Tehran, Fouman, Iran
2
Institute of Petroleum Engineering, Faculty of Chemical Engineering, College of Engineering, University of Tehran, Tehran, Iran
3
Department of Molecular Medicine, Pasture Institute of Iran, Tehran, Iran
use of an advanced computational technique is very useful and efficient. Quantitative structure–activity relationship (QSAR) methodology is a statistical method that used to describe the correlation betwe
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