Available online at www.scholarsresearchlibrary.com Scholars Research Library Der Pharmacia Lettre, 2012, 4 (4):1246-1269 (http://scholarsresearchlibrary.com/archive.html) ISSN 0975-5071 USA CODEN: DPLEB4 1246 Scholar Research Library Quantitative structure activity relationship (QSAR) of cardiac glycosides: the development of predictive in vitro cytotoxic activity model Amitha Joy and Md. Afroz Alam Department of Biotechnology, Sahrdaya College of Engineering and Technology, Kodakara- 680684, Thrissur, India _____________________________________________________________________________________________ ABSTRACT Cardiac glycosides are group of natural products found to be effective against various cancers. The aim of this study is to propose a binding mode for different conformation of cardiac glycoside analogues to Na + , K + - ATPase pump which is an important target for various cancer cell lines. Quantitative structure activity relationships model were developed with the cytotoxic activity (Expt. IC 50 ) of 19 compounds based on molecular descriptors like docking score, binding free energy, ADME properties, eMBRAcE solvation model, and pharmacophore based 3D QSAR. In the cases of docking score and binding free energy, the correlation coefficient (R 2 ) was in the range of 0.65–0.98 indicating good data fit, cross validation coefficient (q 2 ) in the range of 0.64-0.99 and RMSE was in the range of 0.00–0.36 indicating that the predictive capabilities of the models were acceptable. The prediction model developed for the 226 conformers using docking score and binding free energy showed R 2 in the range of 0.70-0.71, q 2 in the range of 0.69-0.71 and RMSE in the range of 0.22-0.28 indicating acceptable prediction capabilities. In addition, a linear correlation was observed between the predicted and experimented pIC 50 based on ADME properties with R 2 of 0.88, and q 2 of 0.73 and RMSE = 0.32. The prediction model developed for 226 conformers using ADME properties indicated a better fit with R 2 =0.99, q 2 = 0.99 and RMSE = 0.28. Further the prediction model developed using liaison showed, R 2 =0.90, q 2 =0.86, and RMSE=0.23; R 2 =0.59, q 2 =0.34 and RMSE= 0.45 for original and conformers respectively showing good to non linear response. The prediction model developed using eMBRAcE showed R 2 = 0.82, q 2 = 0.79 and RMSE= 0.28; R 2 = 0.89, q 2 = 0.89 and RMSE= 0.20 for original and conformers justify the solvation model parameters are good to use. Finally all the models were validate by pharmacophore based 3D QSAR model for the 19 cardiac glycosides in which the best hypothesis generated correlation coefficient, R 2 =0.9733 which is acceptable pharmacophore features . Low level of RMSE and significant R 2 and q 2 values between Expt. IC 50 and Predicted IC 50 revealed that the best quality fit based upon all above said approach. Keywords: ADME, binding free energy, docking, eMBRAcE, liaison, prediction model _____________________________________________________________________________________________ INTRODUCTION 1.1 Cardiac glycosides Cardiac glycosides are a group of natural products occurring in a limited number of plant families and are characterized by their ability to inhibit membrane-bound sodium-potassium activated ATPase [5]. Their continued efficacy in treatment of congestive heart failure and as anti-arrhythmic agents is well appreciated. Less well known however, is the emerging role of this category of compounds in the prevention and /or treatment of proliferative diseases such as cancer [11]. From an ethnopharmacological perspective it may be noted that leaves of Digitalis purpurea (containing digoxin) have been used traditionally to treat tumors in different parts of the world [5]. Digitalis glycosides are one of the most useful groups of drugs in therapeutics [10]. The pharmacodynamic properties of digitalis glycosides include inotropic effect, chronotropic effect and toxic and/or side effects [2]. In contrast, it is used for the treatment of heart failure, preclinical and retrospective patient data suggest that cardiac