Tuberculosis - 1RRI-Q1 - 7,8-Dihydroneopterin Aldolase

Respiratory Diseases
1RRI-Q1
7,8-Dihydroneopterin Aldolase

7,8-Dihydroneopterin Aldolase ( DHNA ) has no human equivalent but is an essential enzyme in bacteria including Mycobacterium Tuberculosis, playing a critical role in folate synthesis. This is a novel antibacterial target which is interesting because bacteria in contrast to humans (and other mammals) cannot absorb folate from their environment. Without folate bacteria cannot grow! This query is based on a different crystal structure to 1nbu-q1.

This query gives above average number of hits and longer than typical job times.


W J Sanders et al J Med Chem (2004) 47.7 p1709-18

Cancer - 1BQO-Q1 - Stromelysin

Cancer
1BQO-Q1
Stromelysin

Stromelysin belongs to the class of Matrix MetallogProteinases (MMPs). It is a recognised anti-cancer target which is associated with tumour blood supply although finding clinically effective molecules has proven difficult. This query is based on a different protein crystal structure to 1b8y-q1 and 1biw-q1.

The times for test jobs were variable often giving more hits than average.

R C Rizzo et al J Med Chem (2004) 47.12 p3065-74

Arthritis - 1FXF-Q1 - Phospholipase A2 (PLA2)

Proteome
1FXF-Q1
Phospholipase A2 (PLA2)

Phospholipase A2 (PLA2) cleaves ester bond in glycerophospholipids releasing free fatty acids and lysophospholipids. Excessive levels of human nonpancreatic PLA2 has been associated with a number of disease states including arthritis, septic shock and atherosclerosis. Inhibition of PLA2 may have therapeutic potential in the treatment of arthritis. This query is based on a different crystal structure than 1fx9-q1.

For test jobs, times and numbers of hits for this query where typical.


J S Sawyer et al J Med Chem (2005) 48.3 p893-6

HIV - 1BDQ-Q1 - HIV Protease

HIV
1BDQ-Q1
HIV Protease

HIV protease is a recognised drug target. However, mutations of this protein render many of the inhibitors ineffective against mutant strains.

We expect this query to give above normal numbers of hits and below average job times on a typical PC.

A B Smith III, J Med Chem (2003) 46.10 p1831-44

Useful Chemisty

Useful Chemistry is using some of our result information for HIV & Malaria.

That's about all I know so go visit and have a read

Useful Chemisty Website

Cancer - 1O4P-Q1 - C-SRC Tyrosine Kinase

Cancer
1O4P-Q1
C-SRC Tyrosine Kinase

Tyrosine kinases occur widely in human tissues. Achieving selectivity is important to avoid side-effects especially if a drug is to be taken for a long period of time. C-SRC tyrosine kinase is a recognised anti-cancer drug target. This query is based on a different crystal structure to 1lcj-q1.

The job times for test queries varied sometimes taking longer average jobs and giving more hits.

L A Witucki et al Chem Biol (2002) 9.1 p25-33

Methodology - 1E7U-Q4 - Better Hits Included or Not / Cancer

Methodology
1E7U-Q4
Phosphatidylinositol 3 Kinase

Phosphatidylinositol 3 Kinase (PI3K) regulation of the Akt/PKB pathway is essential for cell survival. Inhibition of PI3K leads to apoptosis (cell death) as a consequence Akt/PKB not phosphorylating proteins including Bad, transcription factors, caspase-9 amd ASK-1. There is reason for thinking that cancer cells would be selectively killed by a PI3K inhibitor.

This query is part of a series which explores the use of less stringent queries that give more hits. We hope to gain an insight into whether better hits are generally included. Test jobs for this query took longer and gave more hits than typical jobs.

E H Walker et al (2000) Mol Cell Biol 6 p909

Cancer - 1EAX-Q1 - Matriptase

Cancer
1EAX-Q1
Matriptase

Matriptase belongs to the serine protease family of proteins. It has recently been identified as a cancer target. This query is based on a different crystal structure to 1eaw-q1.

The job times and number of hits for test queries varied.


R Friedrich and W Bode J Biol Chem (2001) 277 p2160

AntiBacterial - 1KZM - Gyrase B

Proteome
1KZM-Q1
Gyrase B

Gyrase is a recognised antibacterial target. However, existing inhibitors have not had therpeutic potential because of serious side-effects and mutant resistance. It may be possible to find alternative inhibitors which do not have these limitations. This query is based on a different crystal structure to 1a6j-q1.

Job times for this query varied with some jobs taking less time and giving fewer hits than average jobs.

A Tanitame et al J Med Chem (2004) 47.14 p3693-6

Cancer - 1EAW-Q1 - Matriptase

Cancer
1EAW-Q1
Matriptase

Matriptase belongs to the serine protease family of proteins. It has recently been identified as a cancer target.

The job times for test queries took longer than average giving more hits.


R Friedrich and W Bode J Biol Chem (2001) 277 p2160




Snipet from the link
http://www.nih.gov/news/pr/aug2005/nidcr-15.htm

Scientists Find Cell Surface Enzyme Matriptase Causes Cancer
Scientists at the National Institute of Dental and Craniofacial Research (NIDCR) and colleagues report in animal studies that a single, scissor-like enzyme called matriptase, when left to its own devices, can cause cancer.

This finding, published in the current issue of the journal Genes and Development, marks the first report of a protein-cleaving enzyme, or protease, on the cell surface that can efficiently trigger the formation of tumor cells. The authors also note that matriptase is the first known cell-surface protease that can act as an oncogene, an umbrella term for mutated genes and their proteins that prompt cells to divide too rapidly, a hallmark of tumor cells.

“What makes matriptase potentially such a good molecular target to treat cancer is its accessibility,” said NIDCR scientist Dr. Thomas Bugge, the senior author on the paper. “We don’t have to trick the tumor cell to internalize a drug, then hope it reaches its destination in an appropriate concentration and duration. In this case, the bull’s eye is right on the cell surface.”


..... follow the link for more

Malaria - 1LS5-Q2 - Range extended

Plasmepsin IV, 1LS5-Q2 a Malaria target has been exteneded, initialy starting with jobs in the range 1550 to 19154.

Plasmodium falciparum (the parasite which causes Malaria) invades erythrocyte cells and consumes the host hemoglobin. Plasmepsin plays a key role digesting the protein and has been recognised as a novel target for anti-malaria drugs. Inhibition of hemoglobin degradation lead to toxic concentrations and parasite death in culture.

Potential Collaborator - Malaria

Think just mentioned he has a potential collaborator who would like to look at the results from jobs 15500 to 19154.

So if you could, switch over to Malaria (1p45-q1 I beleive) for a bit, they should soon be restricted to this subset as well.

Methodology - 1FGI-Q2 - Better Hits ? - Fibroblast Growth Factor Receptor-1

Methodology
1FGI-Q2
?name

Fibroblast growth factor receptor-1 ( FGFr-1 ) is understood to play a role in signalling blood vessel development in which there has been renewed interest recently. It is recognised that VEFGr plays a key role in blood vessel development and it is suggested that inhibition of FGFr-1 may be an alternative to inhibiting VEGFr with fewer side-effects.

This query is part of a series which explores the use of less stringent queries that give more hits. We hope to gain an insight into whether better hits are generally included.
Test jobs gave more hits and took longer than average jobs.

M Mohammadi et al EMBO J (1998) 17 p5896-5904

Malaria has been extended - 1P45-Q1

1P45-Q1 a Malaria target has been extended into a larger set of molecules

Enoyl Reductase (ENR)

In Plasmodium falciparum (the parasite which causes Malaria), Enoyl Reductase (ENR) plays a critical role creating long chain molecules known as fatty acids which are used in the synthesis of cell wall mycolic acids. Effective inhibition of this enzyme has been demonstrated to have therapeutic potential in the treatment of Malaria.

Inhibiting Enoyl Reductase in Mycobacterium tuberculosis would also be effective against drug resistant strains of TB.

Pictures M R Kuo et al J Biol Chem (2003) 278.23 p20851-20859

End of Find-a-Drug FAQ's

End of Find-a-Drug

When will Find-a-Drug end?
The entire project ends on 16 December 2005.
We are obviously very grateful for the contributions of members and will continue to work with our collaborators.

Will the software be automatically uninstalled?
We have tested an automatical uninstall procedure which we plan to make available.

Why is Find-a-Drug ending?
We have processed more than the 250 queries we originally envisaged. We have also targetted most of the recognised protein targets for the major project areas. Where we have been able to obtain experimental data to confirm biological activity, the predictions have exceeded our expectations.
We have concluded that there are insufficient worthwhile protein queries to continue the project into 2006 and have decided to close the project on 16 December 2005. We will continue to make some new queries available over the coming weeks but will not accept results after the close of the project.

Will the forum be available after the project ends?
We see no reason to close it on the 16 December but we do not envisage it to remain available for weeks. Thereafter we will use a notice page at all the usual website addresses.

Is the decision to close Find-a-Drug financial?
No.

Couldn't you process more molecules for existing queries?
The minimum number of molecules we screen (40 million) is already more than 10x the number routinely screened by typical major pharmaceutical companies. Only for carefully selected queries where we have reason to believe that the additional results will be used have we increased the number of molecules screened.

What is happening with the results to date?
We will continue to work with existing partners as well as seek additional collaborations.

How I can find out about progress in the future?
We will handle news of progress on a case by case basis. Any major announcements will be picked by the Distributing Computing news sites.

Cancer - 1LCJ-Q1 - C-SRC Tyrosine Kinase

Cancer
1LCJ-Q1
C-SRC Tyrosine Kinase

Tyrosine kinases occur widely in human tissues. Achieving selectivity is important to avoid side-effects especially if a drug is to be taken for a long period of time. C-SRC tyrosine kinase is a recognised anti-cancer drug target.

The job times for test queries took less time than average giving few hits.

L A Witucki et al Chem Biol (2002) 9.1 p25-33

Queries Left To Do

Just a quick estimate of what new queries we expect to process in the coming weeks:

7 cancer
1 HIV
1 Respiratory Disease (TB)
6 Proteome

We also anticipate some Methodology queries

Find-a-Drug to close on 16 December 2005

Quote Keith Davis (THINK), The Guy in Charge of Find-a-Drug

Find-a-Drug to close on 16 December 2005
The Find-a-Drug project has now processed more queries than the original 250 we envisaged. We have also targetted most of the recognised protein targets for the major project areas. Where we have been able to obtain experimental data to confirm biological activity, the predictions have exceeded our expectations. Our experience suggests that it will be difficult to find collaborators who will be interested in the results of targetting proteins whose biological function is unknown or of little therapeutic interest.

We have concluded that there are insufficient worthwhile protein queries to continue the project into 2006 and have decided to close the project on 16 December 2005. We will continue to make some new queries available over the coming weeks but will not accept results after the close of the project.

We are obviously very grateful for the contributions of members and will continue to work with our collaborators.

Announced
http://www.find-a-drug.org.uk/news.html

and in the forum here
http://www.find-a-drug.org.uk/forums/viewtopic.php?t=5649&highlight=