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Open AccessArticle

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

1
Dompé Farmaceutici SpA, Via Campo di Pile, 67100 L’Aquila, Italy
2
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli, 25, I-20133 Milano, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(7), 2265; https://doi.org/10.3390/ijms21072265
Received: 17 January 2020 / Revised: 19 February 2020 / Accepted: 20 March 2020 / Published: 25 March 2020
(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2020)
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. View Full-Text
Keywords: TRPM8; docking simulations; structure-based virtual screening; multiple receptor conformations; consensus approaches; LiGen™, PLANTS; EFO TRPM8; docking simulations; structure-based virtual screening; multiple receptor conformations; consensus approaches; LiGen™, PLANTS; EFO
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Talarico, C.; Gervasoni, S.; Manelfi, C.; Pedretti, A.; Vistoli, G.; Beccari, A.R. 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, 21, 2265.

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