Abstract
Background: 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.
Highlights
TRPM8 is a tetrameric nonselective cation channel, which is primarily activated by cold through a multimodal mechanism influenced by other factors, such as voltage, pH plus some specific ligands [1,2,3]
The enhancement is greater when using the PLANTS docking results compared to LiGenTM, and this can be explainable by considering that LiGenTM yields very remarkable EF 1% values even by considering single monomers and its performances can be further improved with difficulty
These results suggest that the effect of a linear combination of docking scores is here reaching a plateau condition with four different variables, justifying the choice of avoiding more complex consensus equations that would have very limited effects with the overfitting risk
Summary
TRPM8 is a tetrameric nonselective cation channel, which is primarily activated by cold through a multimodal mechanism influenced by other factors, such as voltage, pH plus some specific ligands (e.g., menthol) [1,2,3]. Mutational analyses allowed a precise characterization of the arrangement of this pocket and the key interacting residues [13] This binding site immediately appeared to be a potentially druggable cavity, especially because its non-conserved residues should permit the rational design of reasonably selective ligands [14]. 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
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