Supervised screening of Tecovirimat-like compounds as potential inhibitors for the monkeypox virus E8L protein

by Selleckchem | Dec 10 2023

Monkeypox virus (MPXV) is a budding public health threat worldwide, and there lacks a personalized drug availability to treat MPXV infections. Tecovirimat, an antiviral drug against pox viruses, is recently confirmed to be effective against the MPXV in vitro using nanomolar concentrations. Therefore, the current study considers Tecovirimat as a reference compound for a machine learning-based guided screening to scan bioactive compounds from the DrugBank with similar chemical features or moieties as the Tecovirimat to inhibit the MPXV E8L surface binding protein. We used AlphaFold2 to model the E8L's 3D structure, followed by the conformational activity investigation of shortlisted drugs through computational structural biology approaches, including molecular docking and molecular dynamics simulations. As a result, we have shortlisted five drugs named ABX-1431, Alflutinib, Avacopan, Caspitant, and Darapalib that effectively engage the MPXV surface binding protein. Furthermore, the affinity of the proposed drugs is relatively higher than the Tecovirimat by having higher docking scores, establishing more hydrogen and hydrophobic bonds, engaging key residues in the target's structure, and exhibiting stable molecular dynamics.Communicated by Ramaswamy H. Sarma.

Comments:

It sounds like you are describing a scientific study that investigates potential drug candidates for treating Monkeypox virus (MPXV) infections. The study involves utilizing computational methods such as molecular docking and molecular dynamics simulations to identify bioactive compounds similar to Tecovirimat, an antiviral drug known to be effective against pox viruses, specifically targeting the MPXV E8L surface binding protein.

Here's a summary of the key points from your description:

1. **Problem:** Monkeypox virus (MPXV) poses a global public health threat, and there is a lack of personalized drugs to treat MPXV infections.

2. **Approach:** The study utilizes Tecovirimat as a reference compound and employs machine learning-based guided screening to identify bioactive compounds from DrugBank with similar chemical features to Tecovirimat. The goal is to inhibit the MPXV E8L surface binding protein.

3. **Methods:**
- **AlphaFold2 Modeling:** The 3D structure of the MPXV E8L protein is modeled using AlphaFold2, a cutting-edge protein folding prediction tool.
- **Computational Structural Biology Approaches:** Various computational techniques, including molecular docking and molecular dynamics simulations, are employed to investigate the conformational activity of shortlisted drugs.

4. **Findings:** Five drugs, namely ABX-1431, Alflutinib, Avacopan, Caspitant, and Darapalib, are identified as potential candidates. These drugs effectively engage the MPXV surface binding protein. They exhibit higher affinity than Tecovirimat, as indicated by higher docking scores, establishment of more hydrogen and hydrophobic bonds, engagement with key residues in the target's structure, and stable behavior in molecular dynamics simulations.

5. **Significance:** This study suggests these five drugs as potential candidates for further research and development as treatments for MPXV infections. The findings could pave the way for the development of personalized drugs to combat this viral threat.

It's important to note that this summary is based on the information provided, and any specific details about the methods, results, or implications of the study would require a more in-depth analysis of the original research article.