Computer-aided identification of dengue virus NS2B/NS3 protease inhibitors: an integrated molecular modelling approach for screening of phytochemicals

Globally, dengue (DENV) fever has appeared as the most widespread vector-borne disease, affecting more than 100 million individuals annually. No approved anti-DENV therapy or preventive vaccine is available yet. DENV NS3 protein is associated with protease activity and is essential for viral replication process within the host cell. NS2B is linked with NS3 protein as a cofactor. Hence, NS3/NS2B is a potential druggable target for developing inhibitors against dengue virus. In the present study, a dataset of Beta vulgaris L.-based natural compounds was developed. Virtual ligand screening of 30 phytochemicals was carried out to find novel inhibitors against the NS2B/NS3 protein. Spatial affinity, drug-likeness, and binding behaviors of selected phytochemicals were analyzed. Post-simulation analysis, including Principal Component Analysis (PCA), MMGBSA, and Co-relation analysis, was also performed to provide deep insight for elucidating protein-ligand complexes. This computer-aided screening scrutinized four potent phytochemicals, including betavulgaroside II, vitexin xyloside, epicatechin, and isovitexin2-O-xyloside inhibitors exhibiting optimal binding with viral NS3/NS2B protein. Our study brings novel scaffolds against DENV NS2B/NS3 of serotype-2 to act as lead molecules for further biological optimization. In future, this study will prompt the exploration and development of adjuvant anti-DENV therapy based on natural compounds.Communicated by Ramaswamy H. Sarma