Albany 2015:Book of Abstracts
June 9-13 2015
©Adenine Press (2012)
Dual Allosteric Inhibitors Jointly Modulate Structure and Dynamics in the Hepatitis C Virus Polymerase
The Hepatitis C Virus (HCV) affects close to 200 million people globally. This growing epidemic urgently requires the development of more effective therapies. The HCV polymerase (gene product NS5B) has served as a valuable target for therapeutics due to its critical role in replicating the viral genome. Numerous studies have identified inhibitors for this enzyme, including several allosteric non-nucleoside inhibitors (NNIs). A therapeutic approach that has gained prominence in recent years is the combined use of multiple inhibitors in order to enhance their inhibitory effects. Nevertheless, the molecular mechanisms responsible for enhanced inhibition of NS5B when multiple inhibitors are involved remain unclear, particularly with regard to NNIs. In this study, we use molecular dynamics simulations to understand the mechanisms that govern inhibition when two allosteric NNIs simultaneously bind to the HCV polymerase. Our results suggest that NS5B is able to simultaneously bind dual NNIs at non-overlapping sites. Even though the two inhibitors induce distinct structural and dynamic changes, they are also able to jointly modulate specific enzyme conformations and dynamics. We observe that the overall affinity when two inhibitors bind is comparable to the sum of individual affinities, suggesting that these inhibitors act in an additive manner. We discuss the ramifications of these findings for optimizing the efficacies of combination therapies targeting the HCV polymerase.
Jodian A. Brown
Department of Chemistry and Biochemistry