AHM 2005 e-Malaria University of Southampton 1 Jeremy Frey

E-Malaria

AHM 2005Jeremy Frey

School of ChemistryUniversity of Southampton

AHM 2005 e-Malaria University of Southampton 2 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-Malaria University of Southampton 3 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-Malaria University of Southampton 4 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

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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

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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

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Interactivity

Core to keeping students involved

Increases the amount learnt, understood and memorized by students

Provides interest

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Supporting Material

Intermolecular forces Drug design Proteins and amino acids Enzymes

AHM 2005 e-Malaria University of Southampton 9 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

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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

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Possible target - block an enzyme that decodes DNA - DHFR

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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

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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?

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System Outline

Distributed computing cycle steeling grid

AHM 2005 e-Malaria University of Southampton 15 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

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AHM 2005 e-Malaria University of Southampton 17 Jeremy Frey

AHM 2005 e-Malaria University of Southampton 18 Jeremy Frey

Molecular Structure File Format Conversion

Convert to middleware model

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Web Server

Workflow

Docking

3D

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Current drug Trimethoprim, score 57.49

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Organo-phosphorous

Score 68.1 Yes but what else

does it bind to – a bit like a nerve gas?

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Peptides as drugs?

Ala-ala-ala (tripeptide)

score 50.15 Suitable as a

drug?

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Docked conformation of Glu-Phe-Ala, score 68.88 surprisingly large value!

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Groups 16

Sites 5

Users 85

Molecules 692

AverageMinimisation Time

9 seconds

Average Docking Time 5 minutes 20 seconds

Statistics

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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

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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

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Related projects Related to other seti@Home 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-Malaria University of Southampton 28 Jeremy Frey

E-MalariaUse 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

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People & Organizations Rob Gledhill Sarah Kent Andrew Milstead Brian Hudson John Metcalfe John Frampton Havant College

Jon Essex Graham Richards CCDC UD JISC EPSRC