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Mining the ChEMBL database: an efficient chemoinformatics workflow for assembling an ion channel-focused screening library.

ABSTRACT: The ChEMBL database was mined to efficiently assemble an ion channel-focused screening library. The compiled library consists of 3241 compounds representing 123 templates across nine ion channel categories. Compounds in the screening library are annotated with their respective ion channel category to facilitate back-tracing of prospective molecular targets from phenotypic screening results. The established workflow is adaptable to the construction of focused screening libraries for other therapeutic target classes with diverse recognition motifs.

SUBMITTER: Mok NY

PROVIDER: S-EPMC3200031 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Mining the ChEMBL database: an efficient chemoinformatics workflow for assembling an ion channel-focused screening library.

Mok N Yi NY Brenk Ruth R

Journal of chemical information and modeling 20111006 10

The ChEMBL database was mined to efficiently assemble an ion channel-focused screening library. The compiled library consists of 3241 compounds representing 123 templates across nine ion channel categories. Compounds in the screening library are annotated with their respective ion channel category to facilitate back-tracing of prospective molecular targets from phenotypic screening results. The established workflow is adaptable to the construction of focused screening libraries for other therape ...[more]

PMID: 21978256

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Project description:The lipid bilayer membranes are Nature's dynamic structural motifs that individualize cells and keep ions, proteins, biopolymers and metabolites confined in the appropriate location. The compartmentalization and isolation of these molecules from the external media facilitate the sophisticated functions and connections between the different biological processes accomplished by living organisms. However, cells require assistance from minimal energy shortcuts for the transport of molecules across membranes so that they can interact with the exterior and regulate their internal environments. Ion channels and pores stand out from all other possible transport mechanisms due to their high selectivity and efficiency in discriminating and transporting ions or molecules across membrane barriers. Nevertheless, the complexity of these smart "membrane holes" has driven researchers to develop simpler artificial structures with comparable performance to the natural systems. As a broad range of supramolecular interactions have emerged as efficient tools for the rational design and preparation of stable 3D superstructures, these results have stimulated the creativity of chemists to design synthetic mimics of natural active macromolecules and even to develop artificial structures with functions and properties. In this Account, we highlight results from our laboratories on the construction of artificial ion channel models that exploit the self-assembly of conformationally flat cyclic peptides (CPs) into supramolecular nanotubes. Because of the straightforward synthesis of the cyclic peptide monomers and the complete control over the internal diameter and external surface properties of the resulting hollow tubular suprastructure, CPs are the optimal candidates for the fabrication of ion channels. The ion channel activity and selective transport of small molecules by these structures are examples of the great potential that cyclic peptide nanotubes show for the construction of functional artificial transmembrane transporters. Our experience to date suggests that the next steps for achieving conceptual devices with better performance and selectivity will derive from the topological control over cyclic peptide assembly and the functionalization of the lumen.

Project description:Humic substances (HS) are complex natural mixtures comprising a large variety of compounds produced during decomposition of decaying biomass. The molecular composition of HS is extremely diverse as it was demonstrated with the use of high resolution mass spectrometry. The building blocks of HS are mostly represented by plant-derived biomolecules (lignins, lipids, tannins, carbohydrates, etc.). As a result, HS show a wide spectrum of biological activity. Despite that, HS remain a 'biological activity black-box' due to unknown structures of constituents responsible for the interaction with molecular targets. In this study, we investigated the antiviral activity of eight HS fractions isolated from peat and coal, as well as of two synthetic humic-like materials. We determined molecular compositions of the corresponding samples using ultra-high resolution Fourier-transform ion cyclotron resonance mass-spectrometry (FTICR MS). Inhibitory activity of HS was studied with respect to reproduction of tick-borne encephalitis virus (TBEV), which is a representative of Flavivirus genus, and to a panel of enteroviruses (EVs). The samples of natural HS inhibited TBEV reproduction already at a concentration of 1 µg/mL, but they did not inhibit reproduction of EVs. We found that the total relative intensity of FTICR MS formulae within elemental composition range commonly attributed to flavonoid-like structures is correlating with the activity of the samples. In order to surmise on possible active structural components of HS, we mined formulae within FTICR MS assignments in the ChEMBL database. Out of 6502 formulae within FTICR MS assignments, 3852 were found in ChEMBL. There were more than 71 thousand compounds related to these formulae in ChEMBL. To support chemical relevance of these compounds to natural HS we applied the previously developed approach of selective isotopic exchange coupled to FTICR MS to obtain structural information on the individual components of HS. This enabled to propose compounds from ChEMBL, which corroborated the labeling data. The obtained results provide the first insight onto the possible structures, which comprise antiviral components of HS and, respectively, can be used for further disclosure of antiviral activity mechanism of HS.

Dataset Information

Mining the ChEMBL database: an efficient chemoinformatics workflow for assembling an ion channel-focused screening library.

Publications

Mining the ChEMBL database: an efficient chemoinformatics workflow for assembling an ion channel-focused screening library.

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