Conformational dynamics and binding free energy analyses unveil a stable flavonoid inhibitor of dengue virus NS5 polymerase

In 2023 dengue reached a historic peak, with millions of infections and thousands of deaths reported worldwide . Health agencies such as the World Health Organization and the U.S. Centers for Disease Control and Prevention continue to monitor the situation, noting ongoing outbreaks into 2024 and 2025  . The 2023 dengue outbreak in Bangladesh was among the notable spikes that year .

Did You Know? The year 2023 was recorded as the worst dengue year on record, with infections numbering in the millions and deaths in the thousands.

Despite the heavy disease burden, researchers have no approved antiviral drug for dengue and are intensifying efforts to discover small‑molecule inhibitors. A prominent target is the viral NS5 RNA‑dependent RNA polymerase (RdRp), which is essential for viral RNA synthesis . Computational screening, molecular docking and molecular dynamics simulations have identified several candidate compounds that bind to NS5 RdRp, including bioflavonoids , phenolic molecules from *Theobroma cacao* , and flavonoids from diverse plant sources .

Early laboratory work also highlighted a small‑molecule that disrupts the interaction between NS3 and NS5, showing broad‑spectrum antiviral activity in vivo . Natural extracts such as *Scutellaria baicalensis* have demonstrated inhibition of dengue replication , and compounds isolated from *Carpolepis laurifolia* have been reported as NS5 RdRp inhibitors . These findings are supported by in‑silico studies that employ tools like Glide, Prime MM‑GBSA and the OPLS3 force field to estimate binding free energies  .

Expert Insight: Samantha Carter notes that the convergence of high‑throughput virtual screening and detailed molecular dynamics is narrowing the gap between candidate identification and experimental validation. Yet, the sheer diversity of natural products and the dynamic nature of NS5 mean that many promising hits must still clear rigorous pre‑clinical hurdles before they can become viable therapies.

Continued surveillance of dengue trends and accelerated drug‑discovery pipelines are critical as the virus spreads across continents. International collaborations that combine epidemiological data with cutting‑edge computational chemistry may pave the way toward the first effective dengue antiviral.

Frequently Asked Questions

Why was 2023 considered the worst year for dengue?

Data published in 2024 documented that 2023 saw millions of dengue infections and thousands of deaths worldwide, marking it as the worst year on record .

What makes the NS5 polymerase a focus for drug development?

NS5 is the dengue virus’s RNA‑dependent RNA polymerase, essential for replicating the viral genome. Inhibiting NS5 can halt viral RNA synthesis, making it a logical target for antiviral compounds .

What progress has been made toward dengue antivirals?

Researchers have identified several small‑molecule inhibitors through computational docking, molecular dynamics, and experimental testing. Examples include a NS3‑NS5 interaction inhibitor with in‑vivo efficacy , natural extracts that suppress replication , and flavonoid‑derived compounds that bind NS5 RdRp in silico .

How do you think emerging computational tools will shape the search for a dengue cure?