The original motivation for the eMalaria project was to bring together school students with university researchers in the hunt for a new anti-malarial drug. The challenge was offered, via the web, to school students to design molecules and test them using a computational drug design approach to see if the molecule might be suitable for further research as an anti-malarial drug. The participants were not merely going to be passive suppliers of computational resources in the model of the very successful cycle stealing grid drug screening systems as pioneered by Graham Richard’s group and followed most recently by the World Community Grid. Instead, they were involved with the design and selection of potential drug molecules so that they could learn more about modern approaches to drug design and development. This necessitated a significant amount of background and tutorial material to support the investigations.
At its core the eMalaria system uses the Cambridge Crystallographic Data Centre and the Gold docking engine Software. The docking program needs to investigate the whole conformational space of the potential drug and its fit into the enzyme active pocket. Gold evaluates the quality of the fit with an energy scoring function. This function takes into account the main contributions to the forces acting between the atoms in the enzyme and the potential drug; the intermolecular forces as well as any strain imposed on the drug molecule.
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With even moderate sized molecules the size of the conformational space is very large. That is, there are very many ways in which the molecule can be twisted without breaking any bonds. Each different shape can produce different interactions between the potential drug and the enzyme pocket. It is a very significant calculation to evaluate these different possible ways in which the drug could bind into the pocket and locate the best fit.
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To support the anticipated computational load and provide a model that would grow in capacity in parallel with the increase in users, we chose to use a cycle steeling grid. Several machines within the University of Southampton initially provided the computational resource. The expectation was that as schools joined the project they would provide additional computational cycles. This was made possible while protecting the commercial code by using the United Devices (UD) software, which ensured that the core Gold code was secure.
To supply the docking engine we originally built software to enable molecules to be drawn and converted from a 2D sketch to a 3D model with a realistic molecular conformation using empirical rules and molecular mechanics and semi-empirical quantum codes. The drug target for the initial studies was the DHFR protein, chosen for the different way the DHFR protein is regulated in mosquitoes and humans, which makes it very suitable as a target to block. The structure of the DHFR protein was obtained from the protein data bank (PDB) and a scoop suitable for docking produced.
The scripts developed set up the computational job, bringing together the molecule submitted by the user with the drug target, and then submitted the job to the UD system. Web interfaces were provided to keep track of the individual’s runs and allowed the 2D, 3D molecular and docked structures to use the very versatile Java based Jmol program. Keeping track of structures and results for each user required some system to identify the users. We were careful to collect no personal information as we had to be sure that we were clear of any data protection requirements, especially in regard to those users who might be under 18 years of age. In subsequent use for undergraduate teaching we linked the eMalaria system to the University (LDAP) authentication system, allowing access to designated students.
The site was designed to be as accessible as possible for students with special educational needs, particularly those with dyslexia. Information is presented in manageable amounts and boxed away from the navigation tools to avoid confusion. The website has been designed to use cascading style sheets (CSS) to allow students to pick the text font, colour and background that makes it easiest for them to read the website. At all times the user’s built in browser settings are able to override the standard website style sheet. This means that if a user has set their computer up to give the best font and colour options for them, our site will follow these instructions. A text only version is available to make the site accessible to students using a screen reader, and the downloadable documents are available as word documents so that font colour and size can be changed before printing if necessary. The site and associated materials have been designed in accordance with the British Dyslexia Association’s guidance, which turned out to provide a good visual feel for all students.
