3D QSAR studies of inhibitors of cholesterol ester transfer protein (CETP) by CoMFA, CoMSIA and GFA methodologies

CETP is a plasma glycoprotein that mediates the transfer of cholesterol ester (CE) from high-density lipoprotein (HDL) to apolipoprotein-B containing lipoproteins such as very low density lipoprotein (VLDL) and low density lipoprotein (LDL) with a balanced exchange of triglycerides. CETP thus plays a potential pro-atherogenic role by moving CE from HDL into pro-atherogenic VLDL and LDL particles, thereby lowering atheroprotective HDL cholesterol. In this example we describe, 3D QSAR studies on phenoxy substituted N-(3-(1,1, 2,2-Tetrafluroethroxy)benzyl)-N-3-phenonxyphenyl)-trifluro-3-amino-2-propanols using GFA, CoMFA and CoMSIA. For the GFA model, thirty molecules were used as training set and eight as test set to evaluate the external predictability of the equations generated using GFA. Various physicochemical descriptors were correlated with the biological activity out of which descriptors belonging to the family of electronic, spatial, structural and conformational were found to be of importance to the activity. We also performed 3D QSAR studies using CoMFA and CoMSIA. The CoMFA analysis was performed by calculating steric and electrostatic interaction energies around a three dimensional grid. In the CoMSIA model, steric, electrostatic, hydrophobic and hydrogen bond donating factors were correlated to the activity and later the favorable and unfavorable regions of interaction were obtained. For both the models, the internal and external predictability was obtained as follows: r(cv)(2) = 0.536 and r(pred)(2) = 0.6 respectively for CoMFA and r(cv)(2) = 0.491 and r(pred)(2) = 0.852 respectively for the CoMSIA analysis. The models obtained may be used as useful tools for predicting whether a molecule of pharmacological interest bears structural features likely to possess CETP inhibitory activity prior to synthesis.