Combining molecular dynamics and docking simulations to develop targeted protocols for performing optimized virtual screening campaigns on the HTRPM8 channel
Articolo
Data di Pubblicazione:
2020
Citazione:
Combining molecular dynamics and docking simulations to develop targeted protocols for performing optimized virtual screening campaigns on the HTRPM8 channel / C. Talarico, S. Gervasoni, C. Manelfi, A. Pedretti, G. Vistoli, A.R. Beccari. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 21:7(2020 Apr).
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.
Tipologia IRIS:
01 - Articolo su periodico
Keywords:
Consensus approaches; Docking simulations; EFO; LiGen™; Multiple receptor conformations; PLANTS; Structure-based virtual screening; TRPM8; Humans; Models, Molecular; Molecular Dynamics Simulation; Protein Binding; Protein Structure, Quaternary; Protein Structure, Tertiary; TRPM Cation Channels
Elenco autori:
C. Talarico, S. Gervasoni, C. Manelfi, A. Pedretti, G. Vistoli, A.R. Beccari
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