Inhibitors of HIV-1 attachment. Part 3: A preliminary survey of the effect of structural variation of the benzamide moiety on antiviral activity

Meanwell, Nicholas A.; Wallace, Owen B.; Wang, Henry; Deshpande, Milind; Pearce, Bradley C.; Trehan, Ashok K.; Yeung, Kap Sun; Qiu, Zhilei; Wright, John J.; Robinson, Brett S.; Gong, Yi; Wang, Hwei Gene Heidi; Blair, Wade; Shi, Pei Yong; Lin, Pin Fang

doi:10.1016/j.bmcl.2009.07.027

Cited by 37 publications

(22 citation statements)

References 17 publications

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“…Overall, our conclusions are likely to provide broad-based insights into the development of novel HIV attachment inhibitors with implications in both fundamental and therapeutically relevant settings. 11, 15, 30-34 …”

Section: Discussionmentioning

confidence: 99%

Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules

et al. 2014

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Here we report on the structure-based optimization of antibody-recruiting molecules targeting HIV gp120 (ARM-H). These studies have leveraged a combination of medicinal chemistry, biochemical and cellular assay analysis, and computation. Our findings have afforded an optimized analog of ARM-H, which is ~1000 fold more potent in gp120-binding and MT-2 antiviral assays than our previously reported derivative. Furthermore, computational analysis, taken together with experimental data, provides evidence that azaindole- and indole-based attachment inhibitors bind gp120 at an accessory hydrophobic pocket beneath the CD4-binding site and can also adopt multiple unique binding modes in interacting with gp120. These results are likely to prove highly enabling in the development of novel HIV attachment inhibitors, and more broadly, they suggest novel applications for ARMs as probes of conformationally flexible systems.

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Section: Discussionmentioning

confidence: 99%

Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules

et al. 2014

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“…Putative binding sites for BMS‐626529 were identified following analysis of resistance mutation data, available AI structure–activity relationships (SARs), and biophysical and biochemical data, as described in the results and discussion section. Guided by these data, the 16 conformational forms of BMS‐626529 were hand‐docked and/or glide‐docked into the gp120 water channel and CD4:F43 binding pocket that are present in the pCD4, bCD4 and LIG structures, and into the central hydrophobic cleft present within the HIV‐1 gp120 UNLIG closed state.…”

Section: Methodsmentioning

confidence: 99%

Homology models of the HIV‐1 attachment inhibitor BMS‐626529 bound to gp120 suggest a unique mechanism of action

et al. 2014

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HIV-1 gp120 undergoes multiple conformational changes both before and after binding to the host CD4 receptor. BMS-626529 is an attachment inhibitor (AI) in clinical development (administered as prodrug BMS-663068) that binds to HIV-1 gp120. To investigate the mechanism of action of this new class of antiretroviral compounds, we constructed homology models of unliganded HIV-1 gp120 (UNLIG), a pre-CD4 binding-intermediate conformation (pCD4), a CD4 bound-intermediate conformation (bCD4), and a CD4/co-receptor-bound gp120 (LIG) from a series of partial structures. We also describe a simple pathway illustrating the transition between these four states. Guided by the positions of BMS-626529 resistance substitutions and structure–activity relationship data for the AI series, putative binding sites for BMS-626529 were identified, supported by biochemical and biophysical data. BMS-626529 was docked into the UNLIG model and molecular dynamics simulations were used to demonstrate the thermodynamic stability of the different gp120 UNLIG/BMS-626529 models. We propose that BMS-626529 binds to the UNLIG conformation of gp120 within the structurally conserved outer domain, under the antiparallel β20–β21 sheet, and adjacent to the CD4 binding loop. Through this binding mode, BMS-626529 can inhibit both CD4-induced and CD4-independent formation of the “open state” four-stranded gp120 bridging sheet, and the subsequent formation and exposure of the chemokine co-receptor binding site. This unique mechanism of action prevents the initial interaction of HIV-1 with the host CD4+ T cell, and subsequent HIV-1 binding and entry. Our findings clarify the novel mechanism of BMS-626529, supporting its ongoing clinical development. Proteins 2015; 83:331–350. © 2014 Wiley Periodicals, Inc.

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“…The 48 inhibitors were collected from published structure activity relationship data reported by Meanwell et al (2009). The given EC 50 values for all compounds were converted to logarithmic scale for further analysis on dataset, using the following formula.…”

Section: Dataset For Analysismentioning

confidence: 99%

“…Meanwell and a co-worker published a structure activity relationship data for indole glyoxamide derivatives as HIV-1 attachment inhibitors (Meanwell et al, 2009). The main objective of this study was to reveal ligand-protein interactions at molecular level and also to correlate the biological activities with the structures.…”

Section: Introductionmentioning

confidence: 99%

Molecular modeling study of HIV-1 gp120 attachment inhibitors

et al. 2011

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The viral glycoprotein 120 (gp120) is a glycoprotein exposed on viral surface. The gp120 is essential for virus entry into cells as it plays a vital role in seeking out specific cell surface receptors for entry. In this article, we performed docking and three-dimensional quantitative structure activity relationship (3D-QSAR) study on a series of 48 indole glyoxamide derivatives as gp120 inhibitors. Docking study revealed that the inhibitor docked deeply into the gp120 cavity rather than Phe43 of cluster of differentiation 4 (CD4). 3D-QSAR methodologies, comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) were utilized to rationalize the structural variations with their inhibitory activities. The docked pose of the most potent molecule (43) was used to determine the structures of other molecules. The CoMFA yielded a model with cross-validated correlation coefficient of (q 2 ) 0.73 and non-crossvalidated correlation coefficient of (r 2 ) 0.89 with optimum number of components (N = 3). The CoMSIA models were obtained with the combination of various parameters. Final model was computed with steric, hydrophobic-and hydrogen-bond acceptor (SHA) parameters with reasonable statistics (q 2 = 0.80, r 2 = 0.94 and N = 5). The predictive power of developed CoMFA and CoMSIA models were assessed by test set (nine molecules). The predictive r pred 2 for CoMFA and CoMSIA model was found to be 0.93 and 0.74, respectively. The generated contour maps were plotted onto the gp120 active site to correlate structural variations with their biological activity in protein environment. Contour map analyses showed the importance of 4-F substitution of indole ring, which made essential electronic interaction with the crucial residue (Trp427). The 3D models could explain nicely the structure-activity relationships of indole glyoxamide analogs. This would give proper guidelines to further enhance the activity of novel inhibitors.

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Inhibitors of HIV-1 attachment. Part 3: A preliminary survey of the effect of structural variation of the benzamide moiety on antiviral activity

Cited by 37 publications

References 17 publications

Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules

Illuminating HIV gp120-ligand recognition through computationally-driven optimization of antibody-recruiting molecules

Homology models of the HIV‐1 attachment inhibitor BMS‐626529 bound to gp120 suggest a unique mechanism of action

Molecular modeling study of HIV-1 gp120 attachment inhibitors

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