The TDR Targets Database

This is a set of public queries intented to illustrate how to
share lists of targets and query sets.

This set contains 4 queries that return different lists of Plasmodium
genes: enzymes (genes with any EC number); genes absent in human/mouse;
genes that orthologs in Mycobacterium that are essential; and genes
that have orthologs in E. coli that are essential.

Finally, a fifth query is also included in the published set that
is the result of ranking all the genes retrieved by these 4 queries.

The UNION of queries 1-4 has been ranked according to the following
scoring scheme:
Plasmodium enzymes: 20
Plasmodium absent in human/mouse: 50
Plasmodium essential in Mycobacterium: 30
Plasmodium essential in E. coli: 30

All the scores are additive.

Feel free to use these queries for your own good.

Ranked list of Mtb genes, by weighting, containg potential targets.

P. falciparum targets generated based on weighted queries on structure, phylogeny, essentilaity and druggability. 4
queries were run with intersection and union of queries.

3 queries run for pfal...

1. pfal enzymes with any essentiality evidence
2. pfal genes with high dindex (>0.8)
3. pfal genes which have no mammalian ortholgs

qureies were weighted with 30, 20 & 10 as scores and then the UNION of the 3 queries was taken.

Enzymes from T brucei for which there is some structural info avail (actual or model), Cmpd desireability >0.5,
Druggability >0.7, and <2 Transmembrane domains

This is a list of P fal enzymes (EC any) with <2 Tm segments and are essential in some model organism with Cmpd
desireability index of >0.5 a druggability index of >0.7 and with either modeled or an actual structure.

I have run a number of queries using different criteria to
retrieve T. cruzi genes.

Each query filters genes based on a single criteria.

These are:
* gene does not have orthologs in human/mouse [50]
* gene has orthologs in T. brucei [40]
* gene has orthologs in Yeast that are essential [50]
* gene has orthologs in Bacteria (E. coli, M. tuberculosis)
that are essential [40]
* gene has 3D Model(s) [30]
* gene has 3D structure(s) [40]
* gene has a druggability index > 0.6 (0-1 scale) [40]

A ranked list of genes was produced by asking for the UNION
of the above queries and assigning a weight (score) to each query
(in square brackets above).

Feel free to use this set, add/remove queries, revise my scoring scheme,
etc. And do share back your revised sets!

A set of attributes potentially relevant to T. brucei drug target design, including:
- enzymes [100]
- MW <100 kDa [20]
- no TM domains [20]
- structure available in PDB [50]
- model available in ModBase [30]
- present in all TriTryps [25]
- NOT in human [25]
- essentiality evidence in some (other) organism(s) [40]
- essential in T. brucei (lethal RNAi or KO phenotype) [50]
- druggability evidence inferred from orthology (>0.6) [35]
- compound desirability inferred from orthology (>0.3) [35]
- publications in PubMed [35]

TB prioritized targets

The aim of the survey is to capture, collate and make publicly available expert knowledge on potential drug targets
against Human African Trypanosomiasis (HAT). This survey is part of the WHO-TDR Drug Targets Networks
community-wide
strategy to build a prioritise portfolio of tropical disease drug targets. The idea to survey the scientific
community
came from a workshop on Drug Discovery for Trypanosomatid Diseases, held in Dundee in February 2007.

Groups engaged in drug discovery against HAT need to access the best possible drug targets and to contact and
collaborate with experts on that target. This portal is an opportunity to (a) make the community aware of specific
molecular targets and (b) state whether or not you are engaged in, or would be interested in collaborating on, a
drug discovery project related to that target.

This survey on HAT is a pilot scheme. If is considered successful, it may be extended to many other neglected
diseases.

List of suggested targets

Currently NO experimental genetic or chemical evidence

Tb927.8.3530 Glycerol-3-phosphate dehydrogenase – NAD-dependent Paul A Michels
Tb927.1.3830 Glucose-6-phosphate isomerase Paul A Michels
Tb927.5.890 Oligosaccharyl transferase (OST) subunit Michael A Ferguson
Tb927.5.900 Oligosaccharyl transferase (OST) subunit Michael A Ferguson
Tb927.5.910 Oligosaccharyl transferase (OST) subunit Michael A Ferguson

Genetic AND chemical evidence

Tb10.389.1360 Glutamate-cysteine ligase Margaret A Phillips
Tb927.6.4410 S-adenosylmethionine decarboxylase Margaret A Phillips
Tb927.6.4460 S-adenosylmethionine decarboxylase Margaret A Phillips
Tb927.1.1240 cytidine triphosphate synthase Gavin A Whitlock
Tb927.1.700 Phosphoglycerate kinase (glycosomal, isoenzyme C) Paul A Michels
Tb11.01.6980 Vps34 (phosphatidylinositol 3-kinase catalytic subunit) Mark Field
Tb927.6.4280 Glyceraldehyde-3-phosphate dehydrogenase (glycosomal) Paul A Michels
Tb927.6.4300 Glyceraldehyde-3-phosphate dehydrogenase (glycosomal) Paul A Michels
Tb10.6k15.3640 Alternative oxidase Christiine E Clayton
Tb927.7.3360 farnesyl pyrophosphate synthase Roberto Docampo
Tb09.160.4300 solanesyl diphosphate synthase Roberto Docampo
Tb10.61.3140 Glycogen Synthase Kinase Frederick S Buckner
Tb11.01.0330 Aurora kinase-1 Larry Ruben
Tb11.01.5300 Ornithine decarboxylase Margaret A Phillips
Tb10.70.6220 Histone deacetylases David Horn
Tb927.2.2190 Histone deacetylases David Horn
Tb10.406.0520 Trypanothione reductase Alan H Fairlamb
Tb09.160.3590 Cyclic nucleotide specific phsphodiesterase Thomas Seebeck
Tb09.160.3630 Cyclic nucleotide specific phsphodiesterase Thomas Seebeck
Tb10.70.5820 Hexokinase 1 James C Morris
Tb10.61.2550 N-myristoyl transferase Andrew L Hopkins
Tb927.7.460 Protein farnesyltransferase beta subunit Wesley C Van Voorhis
Tb927.3.4490 protein farnesyltransferase alpha subunit Wesley C Van Voorhis
Tb11.01.3900 GlcNAc-PI de-N-acetylase Michael A Ferguson

Genetic OR chemical evidence

Tb927.4.1140 PI4 Kinase III beta Margaret A Phillips
Tb927.7.7420 ATP synthase F1, alpha subunit Achim Schnaufer
Tb927.3.1380 ATP synthase F1, beta subunit Achim Schnaufer
Tb10.70.2210 CRK3:CYC6 Jeremy C Mottram
Tb10.61.3060 GPI:protein transamidase Jeremy C Mottram
Tb927.5.800 TbCK1.2 (Caesin Kinase 1.2) Michael D Urbaniak
Tb927.5.790 TbCK1.2E (Caesin Kinase 1.2) Michael D Urbaniak
Tb10.100.0130 Peroxin 14 (PEX14) Paul A Michels
Tb927.5.1100 Peroxin 5 (PEX5) Paul A Michels
Tb10.61.2680 Pyruvate kinase Paul A Michels
Tb10.6k15.2620 Phosphoglycerate mutase Paul A Michels
Tb927.3.3270 Phosphofructokinase Paul A Michels
Tb10.70.4740 Enolase Paul A Michels
Tb10.70.1370 Fructose-1,6-bisphosphate aldolase Paul A Michels
Tb10.70.5200 Glucose-6-phosphate dehydrogenase Paul A Michels
Tb927.2.3270 Invariant surface glycoprotein Mark Carrington
Tb927.2.3280 Invariant surface glycoprotein Mark Carrington
Tb927.2.3290 Invariant surface glycoprotein Mark Carrington
Tb927.2.3300 Invariant surface glycoprotein Mark Carrington
Tb927.2.3310 Invariant surface glycoprotein Mark Carrington
Tb927.2.3320 Invariant surface glycoprotein Mark Carrington
Tb11.02.3210 Triosephosphate isomerase Paul A Michels
Tb927.7.4900 XRNA Christiine E Clayton
Tb927.1.2600 PUF9 Christiine E Clayton
Tb11.03.0580 UBP1 Christiine E Clayton
Tb11.03.0620 UBP2 Christiine E Clayton
Tb927.3.5280 DRBD1 Christiine E Clayton
Tb927.1.4650 CFB2 Christiine E Clayton
Tb927.6.600 MRNA degradation CAF1 deadenylase Christiine E Clayton
Tb927.7.6310 Polo-like kinase Tansy C Hammarton
Tb09.160.4250 TbCPX (peroxiredoxin) Shane R Wilkinson
Tb09.160.4280 TRYP1 (tryparedoxin peroxidase) Shane R Wilkinson
Tb927.7.1120 TbGPXI-A (non-selenium glutathione peroxidase) Shane R Wilkinson
Tb927.7.1130 TbGPXI-B (non-selenium glutathione peroxidase) Shane R Wilkinson
Tb927.7.1140 TbGPXI-C (non-selenium glutathione peroxidase) Shane R Wilkinson
Tb927.3.3760 TbTPNI (tryparedoxin) Shane R Wilkinson
Tb927.3.3780 TbTPNI (tryparedoxin) Shane R Wilkinson
Tb11.01.7550 TbSODB2 (Superoxide metabolism) Shane R Wilkinson
Tb11.01.6660 TbSODB2 (Superoxide metabolism) Shane R Wilkinson
Tb927.2.4370 Trypanothione synthetase Alan H Fairlamb
Tb11.01.4701 Membrane-bound histidine acid phosphatase Peter Overath
Tb927.6.4220 TbMAPK5 Isabel Roditi
Tb11.01.5220 JBP1 (targetting J biosynthesis Piet Borst
Tb927.6.940 Metacaspases Jeremy C Mottram
Tb11.02.0330 UDP-Glucose 4'-Epimerase (GalE) Michael D Urbaniak
Tb09.160.2970 RNA Editing ligase 1 Kenneth D Stuart
Tb11.02.0120 UDP-GlcNAc diphosphorylase Michael A Ferguson

A list of potential Plasmodium protease drug targets.
*NB Relies on the word "protease" or "peptidase" appearing in gene name to identify proteases - maybe also possible
with EC numbers?

The weighting is
In Plasmodium, has a name like “peptidase”: 100
In Plasmodium, has a name like “protease”: 100
has literature: 30
has modelled or solved structure: 50
druggability >0.3: 50
no orthologues in mammals: 50
essential in some organism: 30

•trna Synthetases
•some essentiality data
•druggability > 0.7
•compound desirablility > 0.1

This is simply a set of queries for genes expressed either in the top quintile (80-100%) or the 2nd quintile (60-80%)
for each of the blood-borne stages: early ring, late ring, early schizont, late schizont, early trophozoite, late
trophozoite, and merozoite. Intersections of individual queries can be performed to assess correlations among
stages.

this is a test

This published set contains a comprehensive set of queries from Pfal that have been weighted 1 against all pfal genes
weighted 0. The Query titles are descriptive of the weighting and combinations. This data set is useful for making
a spread sheet of pfal genes with ability to adjust the weighting to allow re-ranking of target genes.

Uses the same criteria and weights as David Roos' T. brucei query and applies them to L. major, i.e.,
- enzymes [100]
- MW <100 kDa [20]
- no TM domains [20]
- structure available in PDB [50]
- model available in ModBase [30]
- present in all TriTryps [25]
- NOT in human [25]
- essentiality evidence in some (other) organism(s) [40]
- essential in Leishmania (lethal RNAi or KO phenotype) [50]
- druggability evidence inferred from orthology (>0.6) [35]
- compound desirability inferred from orthology (>0.3) [35]
- publications in PubMed [35]

This is an example of incorporating literature rankings of targets into TDRtargets.org. In PLoS Comp Biol 2: e61
(2006), S. Hasan et al. generate 3 ranked lists of M. tuberculosis genes, each based on a separate criterion:
metabolic role, whether they are specific to Actinobacteria, and expression during dormancy. My query set includes
a list of Hasan's top 400 genes (top ~10%) for each criterion as well as an intersection showing the genes that
rank in the top 400 for all 3.

Based on PLoS ONE 2: e1189, 2007. The authors first narrowed the Brugia genes down to those with essential orthologs in
E. coli but lacking close homologs in humans. They then ranked these 589 genes with an algorithm based on data on
homology, essentiality, stage-specific expression, druggability, and expressability. My list includes the top 10%
of their rankings.

Within the Validation subsection of the search page, one can search for four types of genetic experiment:
loss-of-function mutant, overexpression, knockout unrecovered, and RNAi/antisense assay. This query set includes a
search for each type, although there is nothing under overexpression or knockout unrecovered. According to the
curation, 16 genes have been studied in a "loss-of-function mutant" way and 248 have been studied by RNAi/antisense
assay. This curation was completed by Takashi Suzuki some time ago (probably by summer of 2007) and thus is
unlikely to include the latest literature findings.