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A sequential high throughput ion channel screening system for drug discovery in neurological and psychiatric disorders

Final Report Summary - ION (A sequential high throughput ion channel screening system for drug discovery in neurological and psychiatric disorders)

The ultimate aim of the ION project was to develop technical systems capable of improving the speed and efficiency of testing chemical compounds which can act on ion channels and that might be used therapeutically. ION would optimise the performance of a sequence of screening experiments instead of focusing on the execution of a single experiment.

The innovative features of the ION systems addressed several points, ranging from the adaptation and the integration of current and emerging electrophysiology equipment to the development of biological target libraries and intelligent software agents proper for interpreting and processing the outcome of a screening experiment for a given biological target and its modulating chemicals.

The specific objectives of the project were the following:
- the improvement of existing and emerging electrophysiology platforms by adapting them to the ION software and libraries. These improved experimental platforms are called ION Experimental platforms (IONEPs). In particular, ION intended to develop an interfacing software agent to standardise the integration of electrophysiology equipment for the application of its approach to high-throughput screening. The study, development and validation of the interfacing agent were prototyped by adapting the mounted combat system (MCS) platform.
- the selection and adaptation of an appropriate software technology (development environment) in order to design and implement the required software agents.

Amongst the most important results achieved were the following:
- the IONEP from work performed in work package four (WP 4) that was an improved ion channel platform. The existing technology based on oocyte recording, used two separate electrodes to maintain and measure changes in current through ion channels in the membrane. A major innovation of the project was to simplify the existing procedure into a one-electrode system. This was then incorporated into an improved version of the Roboocyte platform. New software to cope with the data generated by the experimental platform was also developed. In addition to analysing the data from initial screening, this software would help in the design of subsequent steps in the drug discovery process.
- the ION Target Library (WP 5), that defined the suite of most suitable ion channel targets to discover drugs in a given context of diseases (for the ION project Parkinson, depression, neuropathic pain). The term annotated library means both a structured and unstructured collection of information and documents describing the nature and properties of the considered cell's membrane proteins (ion channels). The ION Target Library covered a relatively small number of ion channels but it provides a vast annotation including information about the behaviour of these proteins both in vitro and in vivo.
- the ION Chemical Library (WP 6), that was a prototype annotated collection of known chemical structures showing pharmacological activity with respect to the ion channels annotated in the targets library. The chemical structures in the library are organised in a proper ontology. In addition the library provides appropriate codification and formatting software to translate any given structure in a codified data file suitable to be processed by the ION Sequential Screening Software.
- the ION Sequential Screening Software (WP 07), that is a software module for the in silicon estimation of the pharmacological activity (IC50) of a given chemical structure in relation to a specific ion channel target. It works as a suite of QSAR models capable of setting the priority for synthesising new compounds and planning an appropriate sequence of new experiments. The module implements standard chemical identifiers capable of describing the compounds.
- the ION Sequential Screening System (WP 8), that is a tentative integration of the ION components: IONEP, Target and Chemical Libraries and Sequential Screening Software. It is based on a number of data interchange software modules which can be operated through a common user interface. The system was designed to ensure in a future version the use of different experimental platforms.

ION introduced two major innovations, namely an easy access to a large set of targets and to an efficient drug discovery process by exploiting a well-designed and implemented library of starting molecular structures and an innovative analysis of the experimental outputs that enable future experiments to be planned more effectively by introducing software agents capable of interpreting the outcome of an experiment and to plan the next experiment in a drug discovery screening sequence. Therefore, the most important innovative feature of ION was the introduction of a suite of new software tools able to accelerate the analysis of the experimental results and the design of the next screening round for drug discovery in ion channels. These software agents were developed for the MCS platform but they can adapt to other platforms, as well.

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