6um8: Difference between revisions

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'''Unreleased structure'''


The entry 6um8 is ON HOLD  until Paper Publication
==HIV Integrase in complex with Compound-14==
<StructureSection load='6um8' size='340' side='right'caption='[[6um8]], [[Resolution|resolution]] 2.33&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6um8]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UM8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6UM8 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1PE:PENTAETHYLENE+GLYCOL'>1PE</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=QCG:(2S)-tert-butoxy[7-(8-fluoro-5-methyl-3,4-dihydro-2H-1-benzopyran-6-yl)-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-6-yl]acetic+acid'>QCG</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=6um8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6um8 OCA], [http://pdbe.org/6um8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6um8 RCSB], [http://www.ebi.ac.uk/pdbsum/6um8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6um8 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.


Authors: Khan, J.A., Kish, K.
Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors.,Li G, Meanwell NA, Krystal MR, Langley DR, Naidu BN, Sivaprakasam P, Lewis H, Kish K, Khan JA, Ng A, Trainor GL, Cianci C, Dicker IB, Walker MA, Lin Z, Protack T, Discotto L, Jenkins S, Gerritz SW, Pendri A J Med Chem. 2020 Feb 21. doi: 10.1021/acs.jmedchem.9b01681. PMID:32081010<ref>PMID:32081010</ref>


Description: HIV Integrase in complex with Compound-14
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[Category: Unreleased Structures]]
</div>
<div class="pdbe-citations 6um8" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Khan, J A]]
[[Category: Kish, K]]
[[Category: Kish, K]]
[[Category: Khan, J.A]]
[[Category: Aid]]
[[Category: Dna integration]]
[[Category: Endonuclease]]
[[Category: Hiv-1 integrase]]
[[Category: Hydrolase]]
[[Category: Ledgf]]
[[Category: Rnaseh]]
[[Category: Transferase]]

Revision as of 09:56, 4 March 2020

HIV Integrase in complex with Compound-14HIV Integrase in complex with Compound-14

Structural highlights

6um8 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection. Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2- and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.

Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors.,Li G, Meanwell NA, Krystal MR, Langley DR, Naidu BN, Sivaprakasam P, Lewis H, Kish K, Khan JA, Ng A, Trainor GL, Cianci C, Dicker IB, Walker MA, Lin Z, Protack T, Discotto L, Jenkins S, Gerritz SW, Pendri A J Med Chem. 2020 Feb 21. doi: 10.1021/acs.jmedchem.9b01681. PMID:32081010[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. Li G, Meanwell NA, Krystal MR, Langley DR, Naidu BN, Sivaprakasam P, Lewis H, Kish K, Khan JA, Ng A, Trainor GL, Cianci C, Dicker IB, Walker MA, Lin Z, Protack T, Discotto L, Jenkins S, Gerritz SW, Pendri A. Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors. J Med Chem. 2020 Feb 21. doi: 10.1021/acs.jmedchem.9b01681. PMID:32081010 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01681

6um8, resolution 2.33Å

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