Amazon Plant‐Derived Compounds Suppressing Dengue NS5 Protein: Insights from Computational Drug Development and Network Pharmacology Approach

Abstract

Dengue, a life‐threatening Flavivirus infection, is rampant across 128 tropical and subtropical regions, annually afflicting millions and causing 20,000 deaths due to inadequate treatments. Despite the FDA‐approved Dengvaxia vaccine, its limitations necessitate novel drug development. Notably, the enzymatic nature of the NS5 protein (PDB ID: 3p97) within DENV, responsible for viral RNA synthesis, makes it a prime drug target. Employing Pharmacoinformatics, Molecular Dynamics Simulations, Quantum Mechanics, and network pharmacology, we screened compounds from NuBBE, the Brazilian Amazon Plant Database, along with reported dengue compounds. Docking yielded promising scores (−11.1 to −2.8) and (−11 to −3.1) kcal/mol, respectively. From 1310 phytochemicals, top compounds emerged: Ramosin, Pectolinarin, hinokinin, and sesamin, boasting scores of −11, −11, −9.7, and −9.6, surpassing Acetaminophen's −5.8. Validated post‐docking interactions used 100 ns Molecular Dynamics Simulations and quantum mechanics. Pharmacokinetics and Toxicity analysis aligned with ADME norms, showing no undue toxicity. Network pharmacology unveiled connections between bioactive chemicals and disease targets. This investigation uncovers the potential of these compounds to inhibit DENV‐3 NS5 protein. In vitro, in vivo, and cell line assays are crucial next steps for specific anti‐dengue drug development.