Quinone oxidoreductases (QRs) are cytosolic enzymes that are targets for anti-cancer and antimalarial drug development. They catalyze two-electron reduction of quinones to hydroquinones using a flavin adenosine dinucleotide cofactor. The redox chemistry involves hydride transfer reactions between a substrate/co-substrate and the flavin ring of the cofactor <i>via</i> a classic one-site ‘ping-pong’ mechanism. This mechanism is unusual; the active-site appears to possess an oscillatory molecular recognition features (towards substrates/co-substrates) as it passes through its oxidative and reductive cycles. During a particular redox half-cycle, the observed changes in active-site properties (both in terms of geometric and dynamic) originate due to the charge separations between flavin ring atoms and the active-site. The redox state of the flavin and the resulting active-site changes are the primary determinants of molecular recognition. Therefore, a reliable model of selective inhibitor screening would require a precise determination of the QR-inhibitor interaction energies and the characterization of protein dynamics. In the present study, a theoretical model of the ‘ping-pong’ kinetics as well as inhibition will be presented. Using standard hybrid quantum/classical simulation tools, the study aimed to develop a dynamics-based computational inhibitor screening model that is reliable and faster. Some successes and limitations of the approach will be presented.

Targeting enzymes exhibiting ‘ping-pong’ kinetic mechanism: A case study with quinone oxidoreductase

2019 Spring National Meeting

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