Targeting envelope proteins of poxviruses to repurpose phytochemicals against monkeypox: An in silico investigation

Abstract

The monkeypox virus (MPXV) has become a major threat due to the increasing global caseload and the ongoing multi-country outbreak in non-endemic territories. Due to limited research in this avenue and the lack of intervention strategies, the present study was aimed to virtually screen bioactive phytochemicals against envelope proteins of MPXV via rigorous computational approaches. Molecular docking, molecular dynamic (MD) simulations, and MM/PBSA analysis were used to investigate the binding affinity of 12 phytochemicals against three envelope proteins of MPXV, viz., D13, A26, and H3. Silibinin, oleanolic acid, and ursolic acid were computationally identified as potential phytochemicals that showed strong binding affinity toward all the tested structural proteins of MPXV through molecular docking. The stability of the docked complexes was also confirmed by MD simulations and MM/PBSA calculations. Results from the iMODS server also complemented the findings from molecular docking and MD simulations. ADME analysis also computationally confirmed the drug-like properties of the phytochemicals, thereby asserting their suitability for consumption. Hence, this study envisions the candidature of bioactive phytochemicals as promising inhibitors against the envelope proteins of the MPXV, serving as template molecules that could further be experimentally evaluated for their efficacy against monkeypox.

Discovery of a Heparan-Sulfate Binding Domain in Monkeypox Virus H3 Protein as a New Anti-poxviral Drug Target

“…This complexity has rendered the molecular details of the interaction between MPXV's H3 and host cell HS elusive. By employing MD simulations and AI-based structural prediction tools such as AlphaFold2, we have overcome these obstacles, revealing key interaction sites-specifically the α-helical domain-and binding mechanisms 16,[52][53][54][55][56][57][58][59] .…”

“…This complexity has rendered the molecular details of the interaction between MPXV’s H3 and host cell HS elusive. By employing MD simulations and AI-based structural prediction tools such as AlphaFold2, we have overcome these obstacles, revealing key interaction sites—specifically the α-helical domain—and binding mechanisms 16,52–59 . Our study demonstrates the feasibility of our comprehensive computational approach in researching viral proteins involved in protein-glycan interactions, offering a promising methodological advancement.…”

“…For example, H3 binds to cell-surface heparan sulfate (HS), which is not only pivotal for MPXV but also represents a potential universal target across orthopoxviruses . Therefore, H3-specific neutralizing monoclonal antibody protects rabbits and immunodeficient mice against lethal poxvirus infections 14 , and novel mpox vaccines have been developed recently with H3 as an important component 15,16 . However, the structural intricacies of the H3-HS interaction are not well-understood, largely due to the dynamic and heterogeneous nature of HS.…”