AHM 2005 e-MalariaUniversity of Southampton1 Jeremy Frey E-Malaria AHM 2005 Jeremy Frey School of Chemistry University of Southampton

AHM 2005 e-MalariaUniversity of Southampton2 Jeremy Frey Malaria Malaria kills over 2 million annually Caused by a parasite and transmitted by mosquitoes Resistance to existing drugs is growing New drugs are needed Computational modeling can speed up process and save laboratory time and costs

AHM 2005 e-MalariaUniversity of Southampton3 Jeremy Frey Why target school pupils? Numbers of pupils choosing science courses are falling Science is perceived as boring, hard and irrelevant to peoples lives Decline is numbers is worrying for the science community and society at large

AHM 2005 e-MalariaUniversity of Southampton4 Jeremy Frey What difference can the e-Malaria project make? Example of chemistry in context Authentic activity Chance drug candidates could go on for in vitro & in vivo tests

AHM 2005 e-MalariaUniversity of Southampton5 Jeremy Frey What does the project provide? Range of supporting texts and links Interactive quizzes Forum Links with university departments Support from project team Drug design tools

AHM 2005 e-MalariaUniversity of Southampton6 Jeremy Frey Resource design Based on feedback from range of project supporters Designed to look contemporary and interesting Accessibility for students with SEN (Special Educational Needs) Interactivity for interest

AHM 2005 e-MalariaUniversity of Southampton7 Jeremy Frey Interactivity Core to keeping students involved Increases the amount learnt, understood and memorized by students Provides interest

AHM 2005 e-MalariaUniversity of Southampton8 Jeremy Frey Supporting Material Intermolecular forces Drug design Proteins and amino acids Enzymes

AHM 2005 e-MalariaUniversity of Southampton9 Jeremy Frey Design Take a suitable enzyme target in the malaria parasite Design small molecule as possible drug ‘Dock’ in to enzyme target to find improved binding Modify to yield drug like molecule

AHM 2005 e-MalariaUniversity of Southampton10 Jeremy Frey The Target - DHFR Regulates part of DNA synthesis Present in both humans and parasites Different regulation methods between humans and parasites make it an excellent target

AHM 2005 e-MalariaUniversity of Southampton11 Jeremy Frey Possible target - block an enzyme that decodes DNA - DHFR

AHM 2005 e-MalariaUniversity of Southampton12 Jeremy Frey Design a possible drug Now have to find the molecule’s real 3D shape Use quantum mechanics program to work out the molecule’s shape

AHM 2005 e-MalariaUniversity of Southampton13 Jeremy Frey 3D shape Now try to dock the drug in to the enzyme active site- but which way round? Lots of ways to try! How well does it bind?

AHM 2005 e-MalariaUniversity of Southampton14 Jeremy Frey System Outline Distributed computing cycle steeling grid

AHM 2005 e-MalariaUniversity of Southampton15 Jeremy Frey Why UD UD software is relatively heavy weight but highly secure Need to be secure to allow us to run the GOLD software This is real and valuable software which must be protected. Don’t have to worry about invalid answers as we can always readily check

AHM 2005 e-MalariaUniversity of Southampton16 Jeremy Frey

AHM 2005 e-MalariaUniversity of Southampton17 Jeremy Frey

AHM 2005 e-MalariaUniversity of Southampton18 Jeremy Frey Molecular Structure File Format Conversion Convert to middleware model

AHM 2005 e-MalariaUniversity of Southampton19 Jeremy Frey Web Server Workflow Docking 3D

AHM 2005 e-MalariaUniversity of Southampton20 Jeremy Frey Current drug Trimethoprim, score 57.49

AHM 2005 e-MalariaUniversity of Southampton21 Jeremy Frey Organo-phosphorous Score 68.1 Yes but what else does it bind to – a bit like a nerve gas?

AHM 2005 e-MalariaUniversity of Southampton22 Jeremy Frey Peptides as drugs? Ala-ala-ala (tripeptide) score Suitable as a drug?

AHM 2005 e-MalariaUniversity of Southampton23 Jeremy Frey Docked conformation of Glu-Phe-Ala, score surprisingly large value!

AHM 2005 e-MalariaUniversity of Southampton24 Jeremy Frey Groups 16 Sites 5 Users 85 Molecules 692 Average Minimisation Time 9 seconds Average Docking Time5 minutes 20 seconds Statistics

AHM 2005 e-MalariaUniversity of Southampton25 Jeremy Frey Issues Instructions to users Competition in the schools Need to provide personal, school and overall summaries Keeping the systems running Robust web server & software Differences between browsers! Log file overload Network problems

AHM 2005 e-MalariaUniversity of Southampton26 Jeremy Frey Why do it? Chance to see what research (or industry) is like Increase confidence Do things you wouldn’t have a chance to do normally Can give valuable experience which puts you ahead of competition at interviews Can be tailored to suit career dreams

AHM 2005 e-MalariaUniversity of Southampton27 Jeremy Frey Related projects Related to other projects Graham Richards drug screen Climate prediction But student designs molecules not just supply computer power to screen someone else’s choice of a possible drug Student sees and plays with input & output More complex exchanges between us and the students, but data volumes not large, but frequent

AHM 2005 e-MalariaUniversity of Southampton28 Jeremy Frey E-Malaria Use Chemistry + e-Science to allow students to search for anti-malarial drugs. Makes use of real industrial strength programs to check if your idea for a drug might work. Uses spare computer power to do the calculations

AHM 2005 e-MalariaUniversity of Southampton29 Jeremy Frey People & Organizations Rob Gledhill Sarah Kent Andrew Milstead Brian Hudson John Metcalfe John Frampton Havant College Jon Essex Graham Richards CCDC UD JISC EPSRC