ArticleChemical biology & drug design2010
Fragment-based screen against HIV protease.
Article in Chemical biology & drug design, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed.
- Article
- Subtype-Specific HIV-1 Protease and the Role of Hinge and Flap Dynamics in Drug Resistance: A Subtype C Narrative.Viruses · 2025Review
- Implications of Fragment-Based Drug Discovery in Tuberculosis and HIV.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Elasticity-Associated Functionality and Inhibition of the HIV Protease.Advances in experimental medicine and biology · 2022Article
- Targeting novel structural and functional features of coronavirus protease nsp5 (3CLThe Journal of general virology · 2021Review
- Flap-site Fragment Restores Back Wild-type Behaviour in Resistant Form of HIV Protease.Molecular informatics · 2018Article
- Mechanism of the Association Pathways for a Pair of Fast and Slow Binding Ligands of HIV-1 Protease.Biochemistry · 2017Article
- Structures of endothiapepsin-fragment complexes from crystallographic fragment screening using a novel, diverse and affordable 96-compound fragment library.Acta crystallographica. Section F, Structural biology communications · 2016Article
- Computational protein-ligand docking and virtual drug screening with the AutoDock suite.Nature protocols · 2016Article
- Identifying binding hot spots on protein surfaces by mixed-solvent molecular dynamics: HIV-1 protease as a test case.Biopolymers · 2016Article
- Parameterization of an effective potential for protein-ligand binding from host-guest affinity data.Journal of molecular recognition : JMR · 2016Article
- Distinguishing binders from false positives by free energy calculations: fragment screening against the flap site of HIV protease.The journal of physical chemistry. B · 2015Article
- Article
- Highly resistant HIV-1 proteases and strategies for their inhibition.Future medicinal chemistry · 2015Review
- Fractal Dimensions of Macromolecular Structures.Molecular informatics · 2014Article
- An allosteric modulator of HIV-1 protease shows equipotent inhibition of wild-type and drug-resistant proteases.Journal of medicinal chemistry · 2014Article
- Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein-ligand binding challenge.Journal of computer-aided molecular design · 2014Article
- Crystallographic fragment-based drug discovery: use of a brominated fragment library targeting HIV protease.Chemical biology & drug design · 2014Article
- Design, synthesis and evaluation of a potent substrate analog inhibitor identified by scanning Ala/Phe mutagenesis, mimicking substrate co-evolution, against multidrug-resistant HIV-1 protease.Biochemical and biophysical research communications · 2013Article
- Exploiting drug-resistant enzymes as tools to identify thienopyrimidinone inhibitors of human immunodeficiency virus reverse transcriptase-associated ribonuclease H.Journal of medicinal chemistry · 2013Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
We have employed a fragment-based screen against wild-type (NL4-3) HIV protease (PR) using the Active Sight fragment library and X-ray crystallography. The experiments reveal two new binding sites for small molecules. PR was co-crystallized with fragments, or crystals were soaked in fragment solutions, using five crystal forms, and 378 data sets were collected to 2.3-1.3 A resolution. Fragment binding induces a distinct conformation and specific crystal form of TL-3 inhibited PR during co-crystallization. One fragment, 2-methylcyclohexanol, binds in the 'exo site' adjacent to the Gly(16)Gly(17)Gln(18)loop where the amide of Gly(17)is a specific hydrogen bond donor, and hydrophobic contacts occur with the side chains of Lys(14)and Leu(63). Another fragment, indole-6-carboxylic acid, binds on the 'outside/top of the flap' via hydrophobic contacts with Trp(42), Pro(44), Met(46), and Lys(55), a hydrogen bond with Val(56), and a salt-bridge with Arg(57). 2-acetyl-benzothiophene also binds at this site. This study is the first fragment-based crystallographic screen against HIV PR, and the first time that fragments were screened against an inhibitor-bound drug target to search for compounds that both bind to novel sites and stabilize the inhibited conformation of the target.
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