Catching a Moving Target: Comparative Modeling of Flaviviral NS2B-NS3 Reveals Small Molecule Zika Protease InhibitorsClick to copy article linkArticle link copied!
- Szymon PachSzymon PachPharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, Berlin 14195, GermanyMore by Szymon Pach
- Tim M. SarterTim M. SarterResearch School of Chemistry, Australian National University, Canberra, ACT 2601, AustraliaMore by Tim M. Sarter
- Rafe YousefRafe YousefPharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, Berlin 14195, GermanyMore by Rafe Yousef
- David SchallerDavid SchallerPharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, Berlin 14195, GermanyMore by David Schaller
- Silke BergemannSilke BergemannPharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, Berlin 14195, GermanyMore by Silke Bergemann
- Christoph ArkonaChristoph ArkonaPharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, Berlin 14195, GermanyMore by Christoph Arkona
- Jörg RademannJörg RademannPharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, Berlin 14195, GermanyMore by Jörg Rademann
- Christoph NitscheChristoph NitscheResearch School of Chemistry, Australian National University, Canberra, ACT 2601, AustraliaMore by Christoph Nitsche
- Gerhard Wolber*Gerhard Wolber*Email: [email protected]Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Straße 2+4, Berlin 14195, GermanyMore by Gerhard Wolber
Abstract
The 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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