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Catching a Moving Target: Comparative Modeling of Flaviviral NS2B-NS3 Reveals Small Molecule Zika Protease Inhibitors
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posted on 2020-03-06, 21:43 authored by Szymon Pach, Tim M. Sarter, Rafe Yousef, David Schaller, Silke Bergemann, Christoph Arkona, Jörg Rademann, Christoph Nitsche, Gerhard WolberThe
pivotal role of viral proteases in virus replication has already
been successfully exploited in several antiviral drug design campaigns.
However, no efficient antivirals are currently available against flaviviral
infections. In this study, we present lead-like small molecule inhibitors
of the Zika Virus (ZIKV) NS2B-NS3 protease. Since only few nonpeptide
competitive ligands are known, we take advantage of the high structural
similarity with the West Nile Virus (WNV) NS2B-NS3 protease. A comparative
modeling approach involving our in-house software PyRod was employed to systematically analyze the binding sites and develop
molecular dynamics-based 3D pharmacophores for virtual screening.
The identified compounds were biochemically characterized revealing
low micromolar affinity for both ZIKV and WNV proteases. Their lead-like
properties together with rationalized binding modes represent valuable
starting points for future lead optimization. Since the NS2B-NS3 protease
is highly conserved among flaviviruses, these compounds may also drive
the development of pan-flaviviral antiviral drugs.
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drug design campaignssoftware PyRodbinding sitesWNV proteasesvirus replicationbinding modesmicromolar affinitymodeling approachWest Nile VirusSmall Molecule Zika Protease InhibitorsZika VirusZIKVmolecule inhibitorsFlaviviral NS 2BComparative ModelingNS 2B proteasecompoundflaviviral infectionslead-like propertiesdynamics-based 3 D pharmacophores
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