OpenSourceTB:OSTB Series 2: Difference between revisions
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==Starting Point== | ==Starting Point== | ||
TCMDC143693 identified by GSK in a high throughput screen (to be published shortly). | |||
[[Image:GSK2290170A.png|thumb|center|250px| | [[Image:GSK2290170A.png|thumb|center|250px|TCMDC143693, the Starting Point for OSTB Series 2]] | ||
===Properties=== | ===Properties=== | ||
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===Known occurrences=== | ===Known occurrences=== | ||
TCMDC143693 was, when this page was created, absent from Google. | |||
Pubchem search leads to a [https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2009176778 patent]. | Pubchem search leads to a [https://pubchem.ncbi.nlm.nih.gov/patents/?id=US2009176778 patent]. | ||
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A prediction of the target was carried out by [http://www.crg.eu/en/programmes-groups/structural-genomics Marc Marti-Renom] and [https://www.ebi.ac.uk/chembl/ ChEMBL] as part of the original HTS paper identifying the compound. | A prediction of the target was carried out by [http://www.crg.eu/en/programmes-groups/structural-genomics Marc Marti-Renom] and [https://www.ebi.ac.uk/chembl/ ChEMBL] as part of the original HTS paper identifying the compound. | ||
The compound ( | The compound (TCMDC143693) has four predictions, three from Marc's approach and one from the ChEMBL’s approach. (The details on how the predictions were identified are in the forthcoming manuscript). | ||
Marc's predictions:<br> | Marc's predictions:<br> | ||
1) O06266 (an epoxide hydrolase). Link: | 1) O06266 (an epoxide hydrolase). Link: TCMDC143693 —> 3TH-S38-3ans_A —> S38-O06266 (i.e. the GSK compound is similar to 3TH in PDB, which was co-crystallized with 3ans (a Human soluble epoxide hydrolase in complex with a synthetic inhibitor). In turn, the model of the Tuberculosis epoxide hydrolase (O06266) was based on 3ans template and the binding site was conserved. Thus, the path links TCMDC143693 to O06266.<br> | ||
2) A2VJ47 (an epoxide hydrolase ephB), | 2) A2VJ47 (an epoxide hydrolase ephB), TCMDC143693 —> 3TH-S38-3ans_A —> S38-A2VJ47 <br> | ||
3) P64411 (Heat shock protein 90, | 3) P64411 (Heat shock protein 90, TCMDC143693 —> 3TH-PFT-3k99_A —> PFT-P64411 <br> | ||
The EBI prediction:<br> | The EBI prediction:<br> | ||
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==Strings== | ==Strings== | ||
''' | '''TCMDC143693''' ClC1=C(C(NCC2=CC=CS2)=O)N=C3C(C(F)(F)F)=CC(C#N)=CN31 InChI=1S/C15H8ClF3N4OS/c16-12-11(14(24)21-6-9-2-1-3-25-9)22-13-10(15(17,18)19)4-8(5-20)7-23(12)13/h1-4,7H,6H2,(H,21,24) LWIBMEYBVJUXDE-UHFFFAOYSA-N <br> | ||
==Licence== | ==Licence== | ||
Revision as of 21:50, 15 February 2015
Starting Point
TCMDC143693 identified by GSK in a high throughput screen (to be published shortly).
Properties
Inherited data from GSK for TCMDC-143693: MIC vs. H37Rv = 10 μM, active against non-replicating TB (>50% inhibition) in 10 experiments out of 13) and with mean PXC50 of 5.2 μM. Toxicity vs. HepG2 was >100 μM. cLogP is 3.1 and (presumably) measured solubility is 72 μg/mL. Chrom LogD (pH 7.4) is 5.21, and molecular weight 385.
Known occurrences
TCMDC143693 was, when this page was created, absent from Google. Pubchem search leads to a patent.
ChEMBL flags up that a search on SureChEMBL reveals that the compound has appeared (along with nearest neighbours) on 2 patents of the same patent family: https://www.surechembl.org/document/US-20090176778-A1/ and https://www.surechembl.org/document/US-20120121540-A1/
Related Structures
Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis
Lead Optimization of a Novel Series of Imidazo(1,2-a)pyridine Amides Leading to a Clinical Candidate (Q203) as a Multi- and Extensively-Drug-Resistant Anti-tuberculosis Agent
Identification of Novel Imidazo(1,2-a)pyridine Inhibitors Targeting M. tuberculosis QcrB
Bactericidal Activity of an Imidazo(1, 2-a)pyridine Using a Mouse M. tuberculosis Infection Model
Predicted Target
A prediction of the target was carried out by Marc Marti-Renom and ChEMBL as part of the original HTS paper identifying the compound.
The compound (TCMDC143693) has four predictions, three from Marc's approach and one from the ChEMBL’s approach. (The details on how the predictions were identified are in the forthcoming manuscript).
Marc's predictions:
1) O06266 (an epoxide hydrolase). Link: TCMDC143693 —> 3TH-S38-3ans_A —> S38-O06266 (i.e. the GSK compound is similar to 3TH in PDB, which was co-crystallized with 3ans (a Human soluble epoxide hydrolase in complex with a synthetic inhibitor). In turn, the model of the Tuberculosis epoxide hydrolase (O06266) was based on 3ans template and the binding site was conserved. Thus, the path links TCMDC143693 to O06266.
2) A2VJ47 (an epoxide hydrolase ephB), TCMDC143693 —> 3TH-S38-3ans_A —> S38-A2VJ47
3) P64411 (Heat shock protein 90, TCMDC143693 —> 3TH-PFT-3k99_A —> PFT-P64411
The EBI prediction:
P96222 (Mtb HTH-type transcriptional regulator Eth) now http://www.uniprot.org/uniprot/P9WMC1 and https://www.ebi.ac.uk/chembl/target/inspect/CHEMBL1772929. The compound shares a lot of structural features found in known actives (activity <=10 μM) for this target in ChEMBL. These features include the thiophene ring, -CF3, pyrrole ring and nitrile.
Synthetic Chemistry
The starting compound was resynthesized according to (Jessica insert and link to lit source). (Jessica describe synthesis and insert scheme here).
Strings
TCMDC143693 ClC1=C(C(NCC2=CC=CS2)=O)N=C3C(C(F)(F)F)=CC(C#N)=CN31 InChI=1S/C15H8ClF3N4OS/c16-12-11(14(24)21-6-9-2-1-3-25-9)22-13-10(15(17,18)19)4-8(5-20)7-23(12)13/h1-4,7H,6H2,(H,21,24) LWIBMEYBVJUXDE-UHFFFAOYSA-N
Licence
Content is CC-BY-4.0.
Contact
To discuss this project or page, see the contact info on the OSTB Main Page
