Combining Molecular Dynamics and Docking Simulations to Develop Targeted Protocols for Performing Optimized Virtual...

Area of Science:

• Computational chemistry
• Structural biology
• Drug discovery

Background:

• Growing interest in TRPM8 ligands for medicinal applications.
• Recent TRPM8 structure resolution enables structure-based in silico studies.
• TRPM8 (Transient Receptor Potential Melastatin 8) is a key target for drug development.

Purpose of the Study:

• To develop a reliable human TRPM8 (hTRPM8) homology model for virtual screening.
• To assess the utility of structure-based virtual screening (VS) for TRPM8 ligand discovery.
• To evaluate the impact of multi-monomer docking on screening performance.

Main Methods:

• Generated a reliable hTRPM8 homology model.
• Performed 1.0 μs molecular dynamics (MD) simulations for model validation and conformation generation.
• Conducted structure-based virtual screening (VS) using multiple docking programs and selected frames.
• Applied consensus approaches (EFO algorithm) to combine docking scores from all monomers.

Main Results:

• The hTRPM8 homology model demonstrated high reliability.
• LiGen™ showed superior performance among tested docking programs.
• Combining docking results from all four monomers significantly improved consensus model accuracy.
• The study identified effective strategies for structure-based VS of TRPM8.

Conclusions:

• The developed hTRPM8 model is suitable for structure-based VS.
• Accounting for inter-monomer cross-talk by docking all monomers enhances VS accuracy.
• This multi-monomer docking strategy is applicable to other quaternary protein structures with identical binding pockets.