6f20: Difference between revisions
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==Complex between MTH1 and compound 1 (a 7-azaindole-4-ester derivative)== | |||
<StructureSection load='6f20' size='340' side='right' caption='[[6f20]], [[Resolution|resolution]] 2.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6f20]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F20 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F20 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=C9E:Ethyl+1H-pyrrolo[2,3-b]pyridine-4-carboxylate'>C9E</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6f20 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f20 OCA], [http://pdbe.org/6f20 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f20 RCSB], [http://www.ebi.ac.uk/pdbsum/6f20 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f20 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/8ODP_HUMAN 8ODP_HUMAN]] Antimutagenic. Acts as a sanitizing enzyme for oxidized nucleotide pools, thus suppressing cell dysfunction and death induced by oxidative stress. Hydrolyzes 8-oxo-dGTP, 8-oxo-dATP and 2-OH-dATP, thus preventing misincorporation of oxidized purine nucleoside triphosphates into DNA and subsequently preventing A:T to C:G and G:C to T:A transversions. Able to hydrolyze also the corresponding ribonucleotides, 2-OH-ATP, 8-oxo-GTP and 8-oxo-ATP.<ref>PMID:10373420</ref> <ref>PMID:10608900</ref> <ref>PMID:11139615</ref> <ref>PMID:12857738</ref> <ref>PMID:22556419</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Recent literature has both suggested and questioned MTH1 as a novel cancer target. BAY-707 was just published as a target validation small molecule probe for assessing the effects of pharmacological inhibition of MTH1 on tumor cell survival, both in vitro and in vivo. (1) In this report, we describe the medicinal chemistry program creating BAY-707, where fragment-based methods were used to develop a series of highly potent and selective MTH1 inhibitors. Using structure-based drug design and rational medicinal chemistry approaches, the potency was increased over 10,000 times from the fragment starting point while maintaining high ligand efficiency and drug-like properties. | |||
Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.,Rahm F, Viklund J, Tresaugues L, Ellermann M, Giese A, Ericsson U, Forsblom R, Ginman T, Gunther J, Hallberg K, Lindstrom J, Persson LB, Silvander C, Talagas A, Diaz-Saez L, Fedorov O, Huber KVM, Panagakou I, Siejka P, Gorjanacz M, Bauser M, Andersson M J Med Chem. 2018 Mar 7. doi: 10.1021/acs.jmedchem.7b01884. PMID:29485874<ref>PMID:29485874</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6f20" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Andersson, M]] | |||
[[Category: Ericsson, U]] | |||
[[Category: Forsblom, R]] | |||
[[Category: Ginman, T]] | |||
[[Category: Hallberg, K]] | |||
[[Category: Lindstrom, J]] | |||
[[Category: Persson, L]] | |||
[[Category: Rahm, F]] | |||
[[Category: Silvander, C]] | |||
[[Category: Talagas, A]] | |||
[[Category: Tresaugues, L]] | |||
[[Category: Viklund, J]] | |||
[[Category: Hydrolase]] | |||
[[Category: Inhibitor]] | |||
[[Category: Nucleotide hydrolase]] | |||
[[Category: Nudix]] | |||
[[Category: Oncology]] | |||
Revision as of 08:10, 8 March 2018
Complex between MTH1 and compound 1 (a 7-azaindole-4-ester derivative)Complex between MTH1 and compound 1 (a 7-azaindole-4-ester derivative)
Structural highlights
Function[8ODP_HUMAN] Antimutagenic. Acts as a sanitizing enzyme for oxidized nucleotide pools, thus suppressing cell dysfunction and death induced by oxidative stress. Hydrolyzes 8-oxo-dGTP, 8-oxo-dATP and 2-OH-dATP, thus preventing misincorporation of oxidized purine nucleoside triphosphates into DNA and subsequently preventing A:T to C:G and G:C to T:A transversions. Able to hydrolyze also the corresponding ribonucleotides, 2-OH-ATP, 8-oxo-GTP and 8-oxo-ATP.[1] [2] [3] [4] [5] Publication Abstract from PubMedRecent literature has both suggested and questioned MTH1 as a novel cancer target. BAY-707 was just published as a target validation small molecule probe for assessing the effects of pharmacological inhibition of MTH1 on tumor cell survival, both in vitro and in vivo. (1) In this report, we describe the medicinal chemistry program creating BAY-707, where fragment-based methods were used to develop a series of highly potent and selective MTH1 inhibitors. Using structure-based drug design and rational medicinal chemistry approaches, the potency was increased over 10,000 times from the fragment starting point while maintaining high ligand efficiency and drug-like properties. Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.,Rahm F, Viklund J, Tresaugues L, Ellermann M, Giese A, Ericsson U, Forsblom R, Ginman T, Gunther J, Hallberg K, Lindstrom J, Persson LB, Silvander C, Talagas A, Diaz-Saez L, Fedorov O, Huber KVM, Panagakou I, Siejka P, Gorjanacz M, Bauser M, Andersson M J Med Chem. 2018 Mar 7. doi: 10.1021/acs.jmedchem.7b01884. PMID:29485874[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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