Novel Antiviral Phytochemicals Against Dengue Virus 2 NS2B‐NS3 Protease: An In Silico Drug Development Approach

Abstract Dengue fever, a viral disease transmitted by mosquitoes, presents a major public health risk in tropical and subtropical regions globally. Currently, there is no treatment to fight against this disease. The dengue virus 2 (DENV2) NS2B‐NS3 protease is critical for viral replication, making it a promising target for drug discovery. This study aims to identify potential inhibitors against the DENV2 NS2B‐NS3 protease using in silico methods, including molecular docking, ADMET analysis, molecular dynamics simulations, MMGBSA, and DFT calculations. We screened 1138 phytochemicals from the NuBBE database against the NS2B‐NS3 protease (PDB ID: 2FOM) and compared their binding affinities to policresulen, reported as DENV2 NS2B‐NS3 protease inhibitor. Four novel phytochemicals: 3′,4′‐methylenedioxy‐7,8‐(2″,2″‐dimethylpyrano)‐flavone; limonianin; gnetin‐B; and 5,4′‐dihydroxy‐3′,5′‐dimethoxy‐6,7‐(2″,2″‐dimethylpyran)flavonen revealed binding affinities of −8.7, −8.0, −7.8, and −7.8 kcal/mol, respectively, surpassing the reference compound's affinity of −7.0 kcal. Additionally, MD simulations over 100 ns confirmed the stability of these compounds bound with the target protein. Moreover, ADMET analysis demonstrated favorable pharmacokinetic and toxicity profiles, whereas MMGBSA and DFT calculations supported their binding consistency and reactivity. In conclusion, this study discovered promising novel phytochemicals against DENV2 NS2B‐NS3 protease, which could serve as potential leads for developing effective antiviral therapies for the treatment of dengue fever.