Comparative QSAR as a Cheminformatics Tool in the Design of Dihydro-Pyranone Based HIV-1 Protease Inhibitors

Protease is a key viral enzyme in the life cycle of retrovirus HIV-1. Different drug cocktails of HIV-1 protease inhibitors (HIV-PI) along with other drugs have improved the survival rate for HIV-1 infected patients. However, the difficult treatment schedule, adverse side effects & emergence of drug-resistant viral mutations make these drugs less efficient and have led to therapeutic failures. Quantitative Structure Activity Relationship ( QSAR) studies are successfully used in drug design and development. In the present study, a cheminformatics analysis of simple QSAR models laterally validated via comparative QSAR approach is used to understand the inherent relationships between the dihydro-pyranone based HIV-1 protease inhibitors (HIV-PI) and their biological activity. This work focuses on the development history of more than 500 dihydro-pyranones based HIV-PIs from available literature to extract vital information. This cumulative quantitative study of the various substituents that were studied in this scaffold provides valuable mechanistic insight regarding its substituents' interaction with protease enzyme binding pockets. We hope this study will contribute significantly in understanding the binding patterns of drug-resistant mutants with Tipranavir, a recently FDA approved dihydro-pyranone based HIV-PI. In addition, it will be useful in the design of new inhibitors.