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Title: Robust Inhibition of Hepatitis C Viral Propagation
Keywords: inverse drug design, substrate envelope hypothesis, Hepatitis C virus, NS3/4A protease, covalent docking, conformational change
Issue Date: 22-Aug-2012
Citation: RAVINDRANATH PRADEEP ANAND (2012-08-22). Robust Inhibition of Hepatitis C Viral Propagation. ScholarBank@NUS Repository.
Abstract: The design of inhibitors subject to bind only within the shape occupied by the substrate has been identified as a useful strategy to avoid drug resistance (termed the substrate envelope hypothesis). We have developed an inverse design approach that searches for optimal binders that satisfy this constraint. The method is applied here to design robust inhibitors for the shallow, solvent-exposed, substrate-binding groove of HCV NS3/4A protease, using a serine trap warhead to covalently anchor the inhibitor scaffold to the protease. This work introduces a novel methodology for the covalent ligand attachment incorporated into the design procedure using a thermodynamic-cycle framework to treat the conformational change. The binding energy calculations revealed that the designed inhibitors remained minimally affected by known prevalent resistance mutations. Our analysis thus validates the substrate envelope hypothesis by demonstrating that systematic design approaches can lead to robust high-affinity inhibitors, even when considering this shallow, solvent-exposed binding site.
Appears in Collections:Ph.D Theses (Open)

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