alexa Rational design of quinazoline-based irreversible inhibitors of human erythrocyte purine nucleoside phosphorylase


Journal of Chemical Biology & Therapeutics

Author(s): Dempcy RO, Skibo EB

Abstract Share this page

Described herein is the rational design of irreversible inhibitors of human erythrocyte purine nucleoside phosphorylase (PNPase). Inhibitor design started with the observation that the amino group of 8-aminoquinazolin-4(3H)-one interacts with enzyme-bound phosphate. This observation correctly predicted that the 5,8-dione (quinone) and 5,8-dihydroxy (hydroquinone) derivatives of quinazolin-4(3H)-ones would enter the active site. The amine-phosphate interaction also served to confirm that a quinazolin-4(3H)-one binds in the PNPase active sites like a purine substrate. From models of the PNPase active site it was possible to design quinazoline-based quinones that undergo a reductive-addition reaction with an active-site glutamate residue. The best inhibitor studied, 2-(chloromethyl)quinazoline-4,5,8(3H)-trione, rapidly inactivates PNPase by a first-order process with an inhibitor to enzyme stoichiometry of 150. The active-site hydroquinone adduct of this inhibitor eliminates a leaving group to afford a quinone methide species positioned to alkylate another active-site glutamate residue. Thus, this inhibitor is designed to cross-link the PNPase active site by reductive addition followed by the generation of an alkylating quinone methide species.

This article was published in Biochem and referenced in Journal of Chemical Biology & Therapeutics

Relevant Expert PPTs

Relevant Speaker PPTs

Recommended Conferences

Peer Reviewed Journals
Make the best use of Scientific Research and information from our 700 + peer reviewed, Open Access Journals
International Conferences 2017-18
Meet Inspiring Speakers and Experts at our 3000+ Global Annual Meetings

Contact Us

© 2008-2017 OMICS International - Open Access Publisher. Best viewed in Mozilla Firefox | Google Chrome | Above IE 7.0 version