High‐Throughput Virtual Screening of Phytochemicals From Indian Medicinal Plants for the Identification of Potential Inhibitors Against NS2B‐NS3 Protease of Dengue Virus

ABSTRACT Dengue is an acute mosquito‐borne viral infection that has become a major health problem worldwide in recent years. Currently, no specific antiviral therapies are available to treat dengue fever. Every year, an enormous number of deaths are reported due to dengue fever. This necessitates the identification of inhibitors against the dengue virus. The RNA genome of DENV is composed of 10,723 nucleotides, which encodes for 10 proteins (three structural proteins and seven nonstructural proteins). The nonstructural NS2B‐NS3 protease complex has been reported to be the most powerful therapeutic target for the development of anti‐dengue drugs. In the present study, a ligand library comprised of 3496 phytochemicals from 160 medicinal plants was subjected to high‐throughput virtual screening against the NS2B‐NS3 protease of dengue virus. The top 25 best‐fit compounds were shortlisted based on their binding affinity, RMSD UB, and LB values. The binding energies of these phytochemicals were found to be within the range of −9.84 to −2.98 kcal/mol. These phytochemicals were further analyzed through site‐specific docking for 100 independent genetic algorithm (GA) runs. With further analysis of hydrogen bond interactions, binding energy, and clustering, the best binding confirmations of the four protein–ligand complexes were identified. It includes 4‐hydroxystrychnine ( Strychnos nux‐vomica , PubChem ID: 211181), andrograpanin ( Andrographis paniculata , PubChem ID: 11666871), norsanguinarine ( Argemone mexicana , PubChem ID: 97679), and pongaglabrone ( Pongamia pinnata , PubChem ID: 10957726). The thermodynamic stability of these protein–ligand complex structures was evaluated using Schrödinger's Desmond (v7.3) molecular dynamics simulation for a duration of 100 ns. These complex structures were identified to be stable throughout 100 ns. With further experimental and clinical investigations, potential inhibitors identified in the present study could be used as effective lead molecules for the development of novel drugs against the dengue virus.