5izc: Difference between revisions
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5izc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5izc OCA], [http://pdbe.org/5izc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5izc RCSB], [http://www.ebi.ac.uk/pdbsum/5izc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5izc ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5izc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5izc OCA], [http://pdbe.org/5izc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5izc RCSB], [http://www.ebi.ac.uk/pdbsum/5izc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5izc ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 muM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained. | |||
Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery.,Linciano P, Dawson A, Pohner I, Costa DM, Sa MS, Cordeiro-da-Silva A, Luciani R, Gul S, Witt G, Ellinger B, Kuzikov M, Gribbon P, Reinshagen J, Wolf M, Behrens B, Hannaert V, Michels PAM, Nerini E, Pozzi C, di Pisa F, Landi G, Santarem N, Ferrari S, Saxena P, Lazzari S, Cannazza G, Freitas-Junior LH, Moraes CB, Pascoalino BS, Alcantara LM, Bertolacini CP, Fontana V, Wittig U, Muller W, Wade RC, Hunter WN, Mangani S, Costantino L, Costi MP ACS Omega. 2017 Sep 30;2(9):5666-5683. doi: 10.1021/acsomega.7b00473. Epub 2017, Sep 11. PMID:28983525<ref>PMID:28983525</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 5izc" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Revision as of 10:05, 18 October 2017
Trypanosoma brucei PTR1 in complex with inhibitor F032Trypanosoma brucei PTR1 in complex with inhibitor F032
Structural highlights
Publication Abstract from PubMedPteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated the potential of a previously identified class of thiadiazole inhibitors of Leishmania major PTR1 for activity against Trypanosoma brucei (Tb). We solved crystal structures of several TbPTR1-inhibitor complexes to guide the structure-based design of new thiadiazole derivatives. Subsequent synthesis and enzyme- and cell-based assays confirm new, mid-micromolar inhibitors of TbPTR1 with low toxicity. In particular, compound 4m, a biphenyl-thiadiazole-2,5-diamine with IC50 = 16 muM, was able to potentiate the antitrypanosomal activity of the dihydrofolate reductase inhibitor methotrexate (MTX) with a 4.1-fold decrease of the EC50 value. In addition, the antiparasitic activity of the combination of 4m and MTX was reversed by addition of folic acid. By adopting an efficient hit discovery platform, we demonstrate, using the 2-amino-1,3,4-thiadiazole scaffold, how a promising tool for the development of anti-T. brucei agents can be obtained. Exploiting the 2-Amino-1,3,4-thiadiazole Scaffold To Inhibit Trypanosoma brucei Pteridine Reductase in Support of Early-Stage Drug Discovery.,Linciano P, Dawson A, Pohner I, Costa DM, Sa MS, Cordeiro-da-Silva A, Luciani R, Gul S, Witt G, Ellinger B, Kuzikov M, Gribbon P, Reinshagen J, Wolf M, Behrens B, Hannaert V, Michels PAM, Nerini E, Pozzi C, di Pisa F, Landi G, Santarem N, Ferrari S, Saxena P, Lazzari S, Cannazza G, Freitas-Junior LH, Moraes CB, Pascoalino BS, Alcantara LM, Bertolacini CP, Fontana V, Wittig U, Muller W, Wade RC, Hunter WN, Mangani S, Costantino L, Costi MP ACS Omega. 2017 Sep 30;2(9):5666-5683. doi: 10.1021/acsomega.7b00473. Epub 2017, Sep 11. PMID:28983525[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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