Pharmacophore modelling-based drug repurposing approaches for monkeypox therapeutics

Area of Science:

• Virology
• Computational Chemistry
• Drug Discovery

Background:

• Monkeypox is a zoonotic viral disease endemic to Central and West Africa.
• No specific cure exists; smallpox antivirals are used for treatment.
• Drug repurposing offers an efficient strategy for identifying novel therapeutics.

Purpose of the Study:

• To identify novel therapeutic compounds for monkeypox from existing drug libraries.
• To computationally screen compounds targeting the Monkeypox virus thymidine monophosphate kinase (VarTMPK).

Main Methods:

• Homology modeling was used to develop the Monkeypox VarTMPK (1MNR) structure.
• Ligand-based pharmacophore generation and molecular docking were performed.
• Molecular dynamics (MD) simulations (100 ns) and ADMET profiling were conducted.

Main Results:

• Five compounds, including tetrahydroxycurcumin, showed high binding affinity to VarTMPK.
• Tetrahydroxycurcumin (ZINC4649679) exhibited the highest binding energy (-9.7 kcal/mol).
• MD simulations confirmed stable protein-ligand complexes and interaction with key residues (Lys17, Ser18, Arg45).
• ADMET predictions indicated the safety of the docked phytochemicals.

Conclusions:

• Tetrahydroxycurcumin is a promising candidate for monkeypox antiviral therapy.
• In silico findings warrant further in vitro and in vivo validation for efficacy and safety.
• Computational drug discovery accelerates the identification of potential treatments for viral diseases.