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Rational Design of Colchicine Derivatives as anti-HIV Agents via QSAR and Molecular Docking

Author(s):

Apilak Worachartcheewan*, Napat Songtawee, Suphakit Siriwong, Supaluk Prachayasittikul*, Chanin Nantasenamat and Virapong Prachayasittikul   Pages 1 - 13 ( 13 )

Abstract:


Background: Human immunodeficiency virus (HIV) is an infective microorganism that causes an acquired immunodeficiency syndrome (AIDS). Therefore, the rational design of inhibitors for preventing the progression of the disease is required.

Objective: This study aims to construct quantitative structure-activity relationship (QSAR) models, molecular docking and newly design of colchicine and derivatives with anti-HIV activity.

Method: A data set of 24 colchicine and derivatives with anti-HIV activity were employed to develop QSAR models using machine learning methods (e.g. multiple linear regression (MLR), artificial neural network (ANN) and support vector machine (SVM)), and to study a molecular docking.

Results: The significant descriptors relating to the anti-HIV activity included JGI2, Mor24u, Gm and R8p+ descriptors. The predictive performance of the models gave acceptable statistical qualities as observed by correlation coefficient (Q2) and root mean square error (RMSE) of leave-one out cross-validation (LOO-CV) and external sets. Particularly, the ANN method outperformed MLR and SVM methods that displayed Q2 LOC-CV and RMSELOO-CV of 0.7548 and 0.5735 for LOOCV set, and Q2Ext 0.8553 and RMSEExt of 0.6999 for external validation. In addition, the molecular docking of virus-entry molecule (gp120 envelope glycoprotein) revealed the key interacting residues of the protein (cellular receptor, CD4) and the site-moiety preferences of colchicine derivatives as HIV entry inhibitors for binding to HIV structure. Furthermore, newly rational design of colchicine derivatives using informative QSAR and molecular docking was proposed.

Conclusion: These findings serve as a guideline for the rational drug design as well as potential development of novel anti-HIV agents.

Keywords:

colchicines, anti-HIV agent, AIDS, rational design, QSAR, molecular docking

Affiliation:

Department of Community Medical Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Department of Community Medical Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Center of Data Mining and Biomedical Informatics, Faculty of Medical Technology, Mahidol University, Bangkok 10700, Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok 10700



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