Enzyme Tunnels and Gates As Relevant Targets in Drug Design

Marques, Sérgio M.; Daniel, Lukáš; Buryška, Tomáš; Prokop, Zbyněk; Brezovský, Jan; Damborský, Jiřı́

doi:10.1002/med.21430

Cited by 71 publications

(75 citation statements)

References 216 publications

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“…Although such a location adds additional constraints for an inhibitors design, it may also provide new opportunities. As described in the latest review by Marques et al, inhibitors can target not only the active site itself but also the tunnels providing access to it [92]. Indeed, our analysis of the deposited structures of hsEH with bound inhibitors indicates such compounds.…”

Section: Discussionmentioning

confidence: 55%

“…It is worth mentioning that F497 residue, which is also a member of the C-2 cluster, potentially works as a gate that separates the Tc/m and Tg tunnels. As described in works by Góra et al, and Marques et al, enzyme gates have multiple molecular functions [91,92]. One of their main function is to control the access of substances to the enzyme's interior.…”

Section: Binding Residue Clustering Based On the Known Crystal Structmentioning

confidence: 99%

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Novel Potential Binding Sites for Selective Inhibitor Design of Human Soluble Epoxide Hydrolase

Bzówka

Mitusińska

Góra

2020

Preprint

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Human soluble epoxide hydrolase (hsEH) has been known to be involved in the hydrolysis of epoxyeicosatrienoic acids (EETs), which are anti-inflammatory and cardioprotective signalling molecules. Since the conversion of EETs into the corresponding diols generates non-bioactive molecules, the enzyme’s inhibition would be beneficial. hsEH quickly became the molecular target, however, the proposed inhibitors directed toward this enzyme have not undergone clinical trials, mostly due to their low solubility in water. Our goal is to indicate new regions, distinct from those already investigated, that could be considered during the development of novel and perhaps more soluble inhibitors of hsEH. To fulfil this goal, we used a combination of classical and mixed-solvent molecular dynamics (cMD and MixMD) simulations and a ligand tracking approach. Such a strategy, considers conformational changes in the interior of the enzyme, extends conformational space of binding cavities, and provides insight into different sets of potential binding modes. By analysis of the local distribution of different molecular probes (water and organic cosolvent molecules), we were able to identify potential binding sites (hot-spots), which can indicate the location of the most important functional groups for the binding of designed inhibitors. The uniqueness of the binding spots was examined by superpositioning the indicated hot-spots with a map of chemical interactions between the known inhibitors and hsEH. We analysed all available crystal structures of hsEHs with inhibitors deposited in the PDB database to gain insight into the binding modes of the known inhibitors and to find similarities and dissimilarities between them. By comparing the results obtained based on the map of chemical interactions, with the regions identified by using cMD and MixMD, we were able to identify regions that have not been targeted by ligands until now and which are promising possible binding sites for polar groups that would be beneficial for inhibitors solubility.

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Section: Discussionmentioning

confidence: 55%

Section: Binding Residue Clustering Based On the Known Crystal Structmentioning

confidence: 99%

Novel Potential Binding Sites for Selective Inhibitor Design of Human Soluble Epoxide Hydrolase

Bzówka

Mitusińska

Góra

2020

Preprint

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“…Detailed tracking and analysis of ligand behavior across MD trajectories of biomolecular systems represent another strategy to enrich the protein design process by highlighting regions crucial for the transport of ligands, i.e., molecular tunnels, channels, and gates [25,77], which determine ligand associations and dissociation mechanisms [78,79]. In such a way, structural hotspot residues can be detected and considered during the protein engineering process to improve protein activity, change selectivity, or stability [80].…”

Section: Analyses Of Ligand Transportmentioning

confidence: 99%

Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering

Surpeta

Sequeiros-Borja

Brezovský

2020

IJMS

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Computational prediction has become an indispensable aid in the processes of engineering and designing proteins for various biotechnological applications. With the tremendous progress in more powerful computer hardware and more efficient algorithms, some of in silico tools and methods have started to apply the more realistic description of proteins as their conformational ensembles, making protein dynamics an integral part of their prediction workflows. To help protein engineers to harness benefits of considering dynamics in their designs, we surveyed new tools developed for analyses of conformational ensembles in order to select engineering hotspots and design mutations. Next, we discussed the collective evolution towards more flexible protein design methods, including ensemble-based approaches, knowledge-assisted methods, and provable algorithms. Finally, we highlighted apparent challenges that current approaches are facing and provided our perspectives on their further development.

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“…being directly involved in the catalytic reaction. As a consequence, they have attracted growing interest among the drug-design community over recent years [16].…”

Section: Introductionmentioning

confidence: 99%

Coarse-grain simulations on NMR conformational ensembles highlight functional residues in proteins

Sacquin-Mora

2019

J. R. Soc. Interface.

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Dynamics are a key feature of protein function, and this is especially true of gating residues, which occupy cavity or tunnel lining positions in the protein structure, and will reversibly switch between open and closed conformations in order to control the diffusion of small molecules within a protein's internal matrix. Earlier work on globins and hydrogenases have shown that these gating residues can be detected using a multiscale scheme combining all-atom classic molecular dynamics simulations and coarse-grain calculations of the resulting conformational ensemble mechanical properties. Here, we show that the structural variations observed in the conformational ensembles produced by NMR spectroscopy experiments are sufficient to induce noticeable mechanical changes in a protein, which in turn can be used to identify residues important for function and forming a mechanical nucleus in the protein core. This new approach, which combines experimental data and rapid coarse-grain calculations and no longer needs to resort to time-consuming all-atom simulations, was successfully applied to five different protein families.

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Enzyme Tunnels and Gates As Relevant Targets in Drug Design

Cited by 71 publications

References 216 publications

Novel Potential Binding Sites for Selective Inhibitor Design of Human Soluble Epoxide Hydrolase

Novel Potential Binding Sites for Selective Inhibitor Design of Human Soluble Epoxide Hydrolase

Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering

Coarse-grain simulations on NMR conformational ensembles highlight functional residues in proteins

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