Pharmacophore generation and atom-based 3D-QSAR of N-iso-propyl pyrrole-based derivatives as HMG-CoA reductase inhibitors |
| |
Authors: | Mahesh Kumar Teli G K Rajanikant |
| |
Institution: | 1. National Centre for Compositional Characterisation of Materials (NCCCM), Bhabha Atomic Research Centre, ECIL PO, Hyderabad, 500 062, AP, India 2. Department of Biochemistry, University College of Science, Osmania University, Hyderabad, 500 007, AP, India
|
| |
Abstract: | Background Coronary heart disease continues to be the leading cause of mortality and a significant cause of morbidity and account for nearly 30% of all deaths each year worldwide. High levels of cholesterol are an important risk factor for coronary heart disease. The blockage of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity by small molecule inhibitors has been shown to inhibit hypercholesterolemia. Herein, we describe the development of effective and robust pharmacophore model and the structure–activity relationship studies of 43N-iso-propyl pyrrole-based derivatives previously reported for HMG-CoA reductase inhibition. Results A 5-point pharmacophore model was developed and the generated pharmacophore model was used to derive a predictive atom-based 3D quantitative structure–activity relationship analysis (3D-QSAR) model for the studied dataset. The obtained 3D-QSAR model has an excellent correlation coefficient value (r 2?=?0.96) along with good statistical significance as shown by high Fisher ratio (F?=?143.2). The model also exhibited good predictive power confirmed by the high value of cross validated correlation coefficient (q 2?=?0.672). Further, pharmacophoric model was employed for virtual screening to identify four potential HMG-CoA reductase inhibitors. Conclusions The QSAR model suggests that electron-withdrawing character is crucial for the HMG-CoA reductase inhibitory activity. In addition to the electron-withdrawing character, hydrogen bond--donating groups, hydrophobic and negative ionic groups positively contribute to the HMG-CoA reductase inhibition. These findings provide a set of guidelines for designing compounds with better HMG-CoA reductase inhibitory potential. |
| |
Keywords: | |
本文献已被 SpringerLink 等数据库收录! |
|