3D-QSAR CoMFA Study on Human Glutaminyl Cyclase Inhibitors
BioChem Press, Munuganti Ravi, Shashi Nayana, Yadavalli Nataraja Sekhar, Nunna Siva Kumari, Shaik Mahmood · 2007
Motivation. Glutaminyl cyclase (QC), besides its crucial role in hormone maturation and its pathophysiological involvement in Alzheimer’s disease, is a new potential drug target. To understand the structural requirements of QC ligands and to design new ligands against human glutaminyl cyclase with enhanced inhibitory potency we performed a 3D–QSAR (quantitative structure–activity relationships) study with comparative molecular field analysis (CoMFA) for a dataset of 50 imidazole derivatives which are inhibitors of human glutaminyl cyclase. Method. Comparative molecular field analysis (CoMFA) QSAR models were computed with Sybyl 6.7v. Results. The 3D–QSAR model has very good statistics, namely leave–one–out (LOO) cross–validated correlation coefficient q 2 = 0.647, non–cross–validated correlation coefficient r 2 = 0.917, and the predicted correlation coefficient r 2 pred = 0.652. Conclusions. Based on the high values for q 2 and r 2 we are confident that the 3D–QSAR model gives good predictions that may be used to design better QC inhibitors. The CoMFA model reveals the most significant correlation of steric and electrostatic fields with biological activities. The information derived from this study provides a tool for guiding further structural modification to obtain more potent inhibitors of QC.