Abstract:
:Clinically relevant Lys103Asn (K103N) mutant frequently observed in HIV-1 reverse transcriptase (RT) confers drug resistance. To obtain useful structural information necessary for targeted-inhibitor design, molecular docking combined with 3D-QSAR CoMFA and CoMSIA was applied to a set of 53 structurally diverse HIV-RT inhibitors. Two strategies were applied to generate 3D-QSAR models. The first strategy is the flexibility-based molecular alignment (FMA), similar to receptor-based alignment, which samples the biological space of K103N mutant HIV-RT. FMA was conducted by docking the compounds to four structural data of mutant HIV-RT with PDB codes: 1SV5, 2IC3, 1FKP and 1FKO, which are co-crystallized according to NNRTI inhibitors such as etravirine, HBY-097, nevirapine, and efavirenz. The best superposition of the compounds to the active site of 1FKP structure suggests specific inhibition of nevirapine-resistance. The second strategy is the dataset division which employs the principal component analysis (PCA) to classify the dataset into training and test sets that yields statistically significant and robust models. The PCA design selection tool by the most descriptive compounds (MDC) outperforms the largest minimum distance (LMD) for the present dataset. Overall, the results demonstrated the feasibility of the two strategies to the present case and hold a promise for its general applicability to future QSAR studies. The generated models are predictive based on reproducible values of the predicted compared with experimental activities. Further, the complementary analysis of contour maps to the mutant HIV-RT binding site suggested the anchor points for binding affinity. The present study introduced the concept 'clamp-flex' for the rational design of targeted-inhibitor to overcome the K103N pan-class resistance mutation. The predictive models offer new insights into binding modes involving the hydrophobicity and flexibility of the active site.
journal_name
Bioorg Med Chem Lettjournal_title
Bioorganic & medicinal chemistry lettersauthors
San Juan AAdoi
10.1016/j.bmcl.2007.11.134subject
Has Abstractpub_date
2008-02-01 00:00:00pages
1181-94issue
3eissn
0960-894Xissn
1464-3405pii
S0960-894X(07)01450-3journal_volume
18pub_type
杂志文章abstract::The structure-based approaches were implemented to design and rationally select the molecules for synthesis and anti-HCV activity evaluation. The systematic structure-activity relationships of previously discovered molecules (types I, II, III) were analyzed to design new molecules (type IV) by bioisosteric replacement...
journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2012.09.072
更新日期:2012-12-15 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2003.09.100
更新日期:2004-03-22 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2009.12.093
更新日期:2010-02-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2012.06.010
更新日期:2012-08-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2004.12.013
更新日期:2005-02-15 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/s0960-894x(03)00757-1
更新日期:2003-10-20 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2014.10.057
更新日期:2014-12-15 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2007.04.046
更新日期:2007-07-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/s0960-894x(03)00598-5
更新日期:2003-09-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2019.126877
更新日期:2020-02-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2007.10.073
更新日期:2008-01-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2014.07.046
更新日期:2014-09-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2009.03.149
更新日期:2009-07-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2007.04.101
更新日期:2007-07-15 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2019.126856
更新日期:2020-02-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/s0960-894x(02)00282-2
更新日期:2002-07-08 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2016.08.085
更新日期:2016-10-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2015.04.061
更新日期:2015-06-15 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2010.08.061
更新日期:2010-10-15 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
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更新日期:2017-12-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2004.01.085
更新日期:2004-04-19 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2006.02.008
更新日期:2006-05-15 00:00:00
abstract::By recruiting the important moiety from Shikonin, a series of novel oxoindoline derivatives S1-S20 have been synthesized for inhibiting H. pylori urease. The most potent compound S18 displayed better activity (IC50 = 0.71 μM; MIC = 0.48 μM) than the positive controls AHA (IC50 = 17.2 μM) and Metronidazole (MIC = 31.3 ...
journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2018.08.025
更新日期:2018-10-15 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2008.09.027
更新日期:2008-10-15 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2011.02.027
更新日期:2011-04-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2010.08.122
更新日期:2010-11-01 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/s0960-894x(01)00177-9
更新日期:2001-05-07 00:00:00
abstract::Biaryl substituted 2,5-diazabicyclo[2.2.1]heptanes have been synthesized and tested for their affinity toward alpha7 neuronal nicotinic receptors (NNRs). SAR studies established that 5-N-methyl substituent, heteroaryl linker and the nature of terminal aryl group are critical for the ligand to achieve potent alpha7 NNR...
journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2010.04.105
更新日期:2010-06-15 00:00:00
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journal_title:Bioorganic & medicinal chemistry letters
pub_type: 杂志文章
doi:10.1016/j.bmcl.2016.07.048
更新日期:2016-09-01 00:00:00