8fcc: Difference between revisions
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8fcc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/HIV_whole-genome_vector_AA1305#18 HIV whole-genome vector AA1305#18]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FCC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FCC FirstGlance]. <br> | <table><tr><td colspan='2'>[[8fcc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/HIV_whole-genome_vector_AA1305#18 HIV whole-genome vector AA1305#18]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8FCC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8FCC FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene>, <scene name='pdbligand=YO9:4-[(9-{4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}-8-oxo-8,9-dihydro-7H-purin-2-yl)amino]benzonitrile'>YO9</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.57Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene>, <scene name='pdbligand=YO9:4-[(9-{4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl}-8-oxo-8,9-dihydro-7H-purin-2-yl)amino]benzonitrile'>YO9</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8fcc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fcc OCA], [https://pdbe.org/8fcc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fcc RCSB], [https://www.ebi.ac.uk/pdbsum/8fcc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fcc ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8fcc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8fcc OCA], [https://pdbe.org/8fcc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8fcc RCSB], [https://www.ebi.ac.uk/pdbsum/8fcc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8fcc ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2, 4, and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC(50) = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC(50) = 2.2-2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2-6.7x). Most importantly, compound 2 exhibited significantly improved phosphate-buffered saline solubility (10.4 muM) compared to ETV and RPV (<<1 muM). Additionally, the binding modes of compounds 2, 4, and 6 to the reverse transcriptase were studied by X-ray crystallography. | Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2, 4, and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC(50) = 2.5, 2.7, and 3.0 nM, respectively), where the low nanomolar activity was retained against HXB2 (EC(50) = 2.2-2.8 nM) and the K103N and Y181C mutated strains (fold change, 1.2-6.7x). Most importantly, compound 2 exhibited significantly improved phosphate-buffered saline solubility (10.4 muM) compared to ETV and RPV (<<1 muM). Additionally, the binding modes of compounds 2, 4, and 6 to the reverse transcriptase were studied by X-ray crystallography. | ||
Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties.,Prener L, Baszczynski O, Kaiser MM, Dracinsky M, Stepan G, Lee YJ, Brumshtein B, Yu H, Jansa P, Lansdon EB, Janeba Z J Med Chem. 2023 | Design and Synthesis of Novel HIV-1 NNRTIs with Bicyclic Cores and with Improved Physicochemical Properties.,Prener L, Baszczynski O, Kaiser MM, Dracinsky M, Stepan G, Lee YJ, Brumshtein B, Yu H, Jansa P, Lansdon EB, Janeba Z J Med Chem. 2023 Feb 9;66(3):1761-1777. doi: 10.1021/acs.jmedchem.2c01574. Epub , 2023 Jan 18. PMID:36652602<ref>PMID:36652602</ref> | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 8fcc" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8fcc" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Reverse transcriptase 3D structures|Reverse transcriptase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||