Computational screening of medicinal plant phytochemicals to discover potent pan-serotype inhibitors against dengue virus

TLDR

Dengue is a deadly viral disease caused by four serotypes, and infection with one serotype predisposes hosts to heterotypic reinfection. The study aimed to identify compounds that inhibit all dengue serotypes through virtual ligand screening. Plant‑derived antiviral compounds were screened against conserved dengue non‑structural proteins NS1, NS3/NS2B, and NS5 using virtual ligand screening, molecular docking, ADMET filtering, and molecular dynamics simulations. Three compounds—Canthin‑6‑one 9‑O‑β‑glucopyranoside, Kushenol W, and Kushenol K—exhibited optimal binding to all three proteins, representing promising broad‑spectrum lead scaffolds.

Abstract

Abstract Emergence of Dengue as one of the deadliest viral diseases prompts the need for development of effective therapeutic agents. Dengue virus (DV) exists in four different serotypes and infection caused by one serotype predisposes its host to another DV serotype heterotypic re-infection. We undertook virtual ligand screening (VLS) to filter compounds against DV that may inhibit inclusively all of its serotypes. Conserved non-structural DV protein targets such as NS1, NS3/NS2B and NS5, which play crucial role in viral replication, infection cycle and host interaction, were selected for screening of vital antiviral drug leads. A dataset of plant based natural antiviral derivatives was developed. Molecular docking was performed to estimate the spatial affinity of target compounds for the active sites of DV’s NS1, NS3/NS2B and NS5 proteins. The drug likeliness of the screened compounds was followed by ADMET analysis whereas the binding behaviors were further elucidated through molecular dynamics (MD) simulation experiments. VLS screened three potential compounds including Canthin-6-one 9-O-beta-glucopyranoside, Kushenol W and Kushenol K which exhibited optimal binding with all the three conserved DV proteins. This study brings forth novel scaffolds against DV serotypes to serve as lead molecules for further optimization and drug development against all DV serotypes with equal effect against multiple disease causing DV proteins. We therefore anticipate that the insights given in the current study could be regarded valuable towards exploration and development of a broad-spectrum natural anti-dengue therapy.