Novak, Jurica; Kandagalla, Shivananda; Sistla, Ramesh (2025) Insights into the Dynamics and Binding Mechanisms of the Alkhumra Virus NS2B/NS3 Protease: A Molecular Dynamics Study. Advanced Theory and Simulations, 8 (7). ISSN 2513-0390
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Abstract
Abstract Alkhumra virus, a zoonotic pathogen in the Flaviviridae family, causes severe hemorrhagic fever in humans, yet vaccines and drugs remain unavailable. The nonstructural protein 2B (NS2B)/nonstructural protein 3 (NS3) NS2B/NS3 protease, essential for virion maturation, represents a promising therapeutic target. Structural and dynamical changes induced by NS2B cofactor binding to the NS3 protein are examined using all-atom molecular dynamics simulations. NS2B binding reduces the flexibility of NS3, particularly in contact regions, without altering its secondary structure. Non-bonding van der Waals and electrostatic interactions are identified as the primary driving forces in cofactor binding. The protonation states of catalytic triad residues significantly affect the active pocket's geometry. A drug repurposing campaign utilizing ensemble docking and molecular dynamics simulations identified three DrugBank compounds as potential NS2B/NS3 protease inhibitors. The catalytic serine residue with a deprotonated hydroxyl group contributes most significantly to the free energy of binding. These findings provide a detailed understanding of the molecular interactions underlying ligand binding to NS2B/NS3, offering valuable insights for developing effective inhibitors.
| Item Type: | Article | ||||||||
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| Uncontrolled Keywords: | Alkhumra virus; drug repurposing; molecular dynamics; NS2B/NS3 protease | ||||||||
| Subjects: | NATURAL SCIENCES > Chemistry NATURAL SCIENCES > Chemistry > Physical Chemistry NATURAL SCIENCES > Chemistry > Theoretical Chemistry INTERDISCIPLINARY AREAS OF KNOWLEDGE > Biotechnology in Biomedicine (natural science, biomedicine and healthcare, bioethics area |
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| Divisions: | Center for Informatics and Computing | ||||||||
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| Depositing User: | Jurica Novak | ||||||||
| Date Deposited: | 02 Sep 2025 06:37 | ||||||||
| URI: | http://fulir.irb.hr/id/eprint/9937 | ||||||||
| DOI: | 10.1002/adts.202401406 |
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