Combining Molecular Dynamics and Docking Simulations to Develop Targeted Protocols for Performing Optimized Virtual Screening Campaigns on The hTRPM8 Channel

Int J Mol Sci. 2020 Mar 25;21(7):2265. doi: 10.3390/ijms21072265.


There is an increasing interest in TRPM8 ligands of medicinal interest, the rational design of which can be nowadays supported by structure-based in silico studies based on the recently resolved TRPM8 structures. Methods: The study involves the generation of a reliable hTRPM8 homology model, the reliability of which was assessed by a 1.0 μs MD simulation which was also used to generate multiple receptor conformations for the following structure-based virtual screening (VS) campaigns; docking simulations utilized different programs and involved all monomers of the selected frames; the so computed docking scores were combined by consensus approaches based on the EFO algorithm. Results: The obtained models revealed very satisfactory performances; LiGen™ provided the best results among the tested docking programs; the combination of docking results from the four monomers elicited a markedly beneficial effect on the computed consensus models. Conclusions: The generated hTRPM8 model appears to be amenable for successful structure-based VS studies; cross-talk modulating effects between interacting monomers on the binding sites can be accounted for by combining docking simulations as performed on all the monomers; this strategy can have general applicability for docking simulations involving quaternary protein structures with multiple identical binding pockets.

Keywords: EFO; LiGen™, PLANTS; TRPM8; consensus approaches; docking simulations; multiple receptor conformations; structure-based virtual screening.

MeSH terms

  • Humans
  • Models, Molecular
  • Molecular Dynamics Simulation
  • Protein Binding
  • Protein Structure, Quaternary
  • Protein Structure, Tertiary
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*


  • TRPM Cation Channels
  • TRPM8 protein, human