Repurposing Anti-Dengue Compounds against Monkeypox Virus Targeting Core Cysteine Protease

Area of Science:

• Virology
• Drug Discovery
• Computational Chemistry

Background:

• Monkeypox virus (MPXV) is a double-stranded DNA virus causing a global public health emergency.
• MPXV belongs to the Orthopoxvirus genus and has spread to non-endemic regions.
• Effective antiviral therapies are crucial for managing MPXV outbreaks.

Purpose of the Study:

• To identify potential inhibitors for the MPXV core cysteine proteinase using a structure-based drug design approach.
• To evaluate the binding affinity and drug-like properties of identified compounds.
• To explore novel therapeutic strategies against MPXV infections.

Main Methods:

• Employed ensemble-based protein-ligand docking to simulate interactions with the MPXV cysteine proteinase.
• Utilized molecular dynamic simulations to confirm binding stability and analyze interaction mechanisms.
• Performed MMGBSA binding free energy calculations and machine learning models for IC50 prediction of analogues.

Main Results:

• Identified two potent inhibitors, CHEMBL32926 and CHEMBL4861364, with high docking scores (-10.7 and -10.9 kcal/mol).
• Confirmed stable binding of inhibitors to the target protein throughout molecular dynamics simulations.
• Discovered analogues with comparable binding affinities, suggesting viable lead compounds for drug development.

Conclusions:

• Structure-based drug design is a promising strategy for discovering novel MPXV inhibitors.
• CHEMBL32926 and CHEMBL4861364 demonstrate significant potential as starting points for MPXV antiviral drug development.
• Further research into these compounds and their analogues could lead to effective treatments for monkeypox.