Quinone oxidoreductases belong to a class of flavin-dependent oxidoreductases, which catalyze the reduction of quinones to hydroquinones using its flavin adenosine dinucleotide (FAD) cofactor. They play pivotal roles by detoxifying the in vivo reactive oxygenated species (ROS) that damage cellular organelles, and stabilize tumor suppressor proteins. Because of these crucial functions, quinone reductases offer great promise for use in anti-tumorigenic drug development. Quinone reductases (QRs) utilize a 'ping-pong' mechanism, wherein one active site catalyzes two opposing hydride transfer reactions involving FAD. Recent studies revealed that flavin's redox state modulates the active site electrostatics and the protein dynamics.<br/>Understanding of the opposing electrostatic and dynamic effects is the key to successful design of molecules that can inhibit the reaction process. While many docking programs exist, it is our intent to surpass classical mechanical based simulations by combining it with a quantum mechanically treated flavin ring and substrate. The core reaction center is embedded in a molecular mechanically-treated active site with a solvent sphere. This quantum mechanical treatment will allow a more accurate description of the electronic as well as dynamics effects than the traditional programs available. With this automated ligand docking tool, we hope to accurately model and predict the effects of novel ligand binding, aiding the screening process of drug development. The setup, methodology, and results will be presented.

Developing an automated QM/MM docking suite for quinone reductases

251st National Meeting (2016)

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