Dataset Information

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

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 ?s 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.

SUBMITTER: Talarico C

PROVIDER: S-EPMC7177470 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Talarico Carmine C Gervasoni Silvia S Manelfi Candida C Pedretti Alessandro A Vistoli Giulio G Beccari Andrea R AR

International journal of molecular sciences 20200325 7

<h4>Background</h4>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. <b>Methods</b>: 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 ( ...[more]

PMID: 32218173

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Project description:(1) Background: Virtual screening campaigns require target structures in which the pockets are properly arranged for binding. Without these, MD simulations can be used to relax the available target structures, optimizing the fine architecture of their binding sites. Among the generated frames, the best structures can be selected based on available experimental data. Without experimental templates, the MD trajectories can be filtered by energy-based criteria or sampled by systematic analyses. (2) Methods: A blind and methodical analysis was performed on the already reported MD run of the hTRPM8 tetrameric structures; a total of 50 frames underwent docking simulations by using a set of 1000 ligands including 20 known hTRPM8 modulators. Docking runs were performed by LiGen program and involved the frames as they are and after optimization by SCRWL4.0. For each frame, all four monomers were considered. Predictive models were developed by the EFO algorithm based on the sole primary LiGen scores. (3) Results: On average, the MD simulation progressively enhances the performance of the extracted frames, and the optimized structures perform better than the non-optimized frames (EF1% mean: 21.38 vs. 23.29). There is an overall correlation between performances and volumes of the explored pockets and the combination of the best performing frames allows to develop highly performing consensus models (EF1% = 49.83). (4) Conclusions: The systematic sampling of the entire MD run provides performances roughly comparable with those previously reached by using rationally selected frames. The proposed strategy appears to be helpful when the lack of experimental data does not allow an easy selection of the optimal structures for docking simulations. Overall, the reported docking results confirm the relevance of simulating all the monomers of an oligomer structure and emphasize the efficacy of the SCRWL4.0 method to optimize the protein structures for docking calculations.

Dataset Information

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

Publications

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

Similar Datasets

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