Digging the past for a clue: A novel in-silico approach for new leads on 4-OH-pyran-2-ones HIV protease inhibitors

COMP 221

Barun Bhhatarai, bhhatarb@clarkson.edu, Department of Chemistry, Clarkson University, 8 Clarkson Avenue, Potsdam, NY 13699-5810 and Rajni Garg, Department of Chemistry & Biochemistry, California State University San Marcos, 333 S. Twin Oaks Valley Rd., San Marcos, CA 92096.
QSAR studies on several series of 4-OH-pyran-2-ones, a non-peptidic HIV-Protease Inhibitors are presented. This in-silico approach has greatly benefited target drug design and development. With the help of robust QSAR models different molecular shape, size, and electronic character of various substituents of the pyranones can be defined. The pyran-2-one scaffold which was derived from 4-OH-coumarines was the basis for the development of Tipranavir, a 4-OH-5,6-dihydropyran-2-one. The various substituents studied in the archaic scaffolds (i.e., pyran-2-ones, cycloalkyl-pyran-2-ones), were not considered in current scaffold dihydropyran-2-one. Comparative study of the spectrum of available synthesized compounds and their activity marked that there are gaps that were not addressed in detail by synthetic methods in the new scaffolds. Our results show that the balance of hydrophobicity (ClogP), volume-dependent-polarizability (CMR) and the steric fit of the compounds are crucial for designing novel more effective inhibitor/lead compounds and simultaneously reducing the number of expensive failures.