DOCK 6: Combining techniques to model RNA–small molecule complexes

Lang, P. Therese; Brozell, Scott R.; Mukherjee, Sudipto; Pettersen, Eric F.; Meng, Elaine C.; Thomas, Veena; Rizzo, Robert C.; Case, David A.; James, Thomas Leroy; Kuntz, Irwin D.

doi:10.1261/rna.1563609

Cited by 664 publications

(665 citation statements)

References 47 publications

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“…Energy minimization was conducted for the protein and ligand with the Amber force field (23,24). For more accurate docking analysis of proteinligands, another docking program, UCSF DOCK 6.5 (25)(26)(27)(28), was used with a flexible algorithm. Before the refined docking experiment, complete energy minimization was performed for the ligands and TACE in Amber force field (23,24).…”

Section: Molecular Docking Analysis Of Tace-tapi-0 and Tace-m8imentioning

confidence: 99%

Matrix Metalloproteinase-8 Plays a Pivotal Role in Neuroinflammation by Modulating TNF-α Activation

Lee

Han

Woo

et al. 2014

The Journal of Immunology

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Matrix metalloproteinases (MMPs) play important roles in normal brain development and synaptic plasticity, although aberrant expression of MMPs leads to brain damage, including blood–brain barrier disruption, inflammation, demyelination, and neuronal cell death. In this article, we report that MMP-8 is upregulated in LPS-stimulated BV2 microglial cells and primary cultured microglia, and treatment of MMP-8 inhibitor (M8I) or MMP-8 short hairpin RNA suppresses proinflammatory molecules, particularly TNF-α secretion. Subsequent experiments showed that MMP-8 exhibits TNF-α–converting enzyme (TACE) activity by cleaving the prodomain of TNF-α (A74/Q75, A76/V77 residues) and, furthermore, that M8I inhibits TACE activity more efficiently than TAPI-0, a general TACE inhibitor. Biochemical analysis of the underlying anti-inflammatory mechanisms of M8I revealed that it inhibits MAPK phosphorylation, NF-κB/AP-1 activity, and reactive oxygen species production. Further support for the proinflammatory role of microglial MMP-8 was obtained from an in vivo animal model of neuroinflammatory disorder. MMP-8 is upregulated in septic conditions, particularly in microglia. Administration of M8I or MMP-8 short hairpin RNA significantly inhibits microglial activation and expression/secretion of TNF-α in brain tissue, serum, and cerebrospinal fluid of LPS-induced septic mice. These results demonstrate that MMP-8 critically mediates microglial activation by modulating TNF-α activity, which may explain neuroinflammation in septic mouse brain.

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Section: Molecular Docking Analysis Of Tace-tapi-0 and Tace-m8imentioning

confidence: 99%

Matrix Metalloproteinase-8 Plays a Pivotal Role in Neuroinflammation by Modulating TNF-α Activation

Lee

Han

Woo

et al. 2014

The Journal of Immunology

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“…Compound 12 is shown in blue. The bound ligand structures were calculated using the DOCK6 suite of dock programs with default parameters (29,31). The substituents occupy the pantetheine-binding pocket consistent with the ILOE data.…”

Section: Conflictingmentioning

confidence: 99%

“…This is shown conceptually in Fig. 6B where DOCK6 was used to build a model of a hypothetical TLM-pantetheine conjugate (yellow) bound to KasA (29,30). As a first step in using the structural data to develop TLM analogs with increased affinity for KasA, we undertook the synthesis of compounds in which the methyl at the 3 position was replaced with a variety of substituents.…”

Section: Conflictingmentioning

confidence: 99%

Thiolactomycin-based β-Ketoacyl-AcpM Synthase A (KasA) Inhibitors

Kapilashrami

Bommineni

Machutta

et al. 2013

Journal of Biological Chemistry

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Background: Potent inhibitors of the tuberculosis drug target KasA are needed. Results: Three-position analogs of the natural product thiolactomycin (TLM) were designed based on transient one-dimensional NOEs that reveal the relative orientation of TLM and a pantetheine analog bound simultaneously to KasA. Conclusion: Three-position analogs of TLM bind to KasA with increased potency. Significance: Optimization of TLM will lead to improved inhibitors of KasA.

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“…We used AmberScore to evaluate the binding energy because AmberScore has been shown to be one of the most precise MD scoring tools for docking studies. 30 The first model had a much lower score, −24, than the second model, which had a score of −14 based on the AmberScore. In contrast, the score of gossypol in the form of (−)-16 was −14, as shown in Figure 4D; this score was lower than the form that is presented in Figure 4C.…”

mentioning

confidence: 92%

Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins

Yue

et al. 2016

ACS Med. Chem. Lett.

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A series of gossypol Schiff bases that were derived from unnatural linear amino acid methyl esters were identified and found to be much more potent than gossypol and ABT-199 in terms of anticancer activity. This is the first example of gossypol Schiff bases with increased activity. The investigation of the Schiff base side chain of gossypol revealed that the unique anticancer effect was achieved by the introduction of hydrophobic ester groups. The optimized products showed low micromolar pan antitumor activities against NCI-60 tumor cell lines, which is promising for further drug development. Studies on the preliminary mechanism of action for their cellular activities was also carried out with antiapoptotic protein (Bcl-2 and Mcl-1) inhibition FP assays. The molecular modeling analysis demonstrated a possible binding mode for these compounds with Bcl-2, which could explain the binding affinity of the novel gossypol Schiff bases with these proteins. KEYWORDS: Gossypol Schiff bases, linear amino acid esters, antiapoptotic proteins N atural polyphenols have received considerable attention because of their biological activity. 1 Gossypol, a polyphenol that is isolated from cotton seeds, has long been investigated for antitumor activity in addition to the reported antiviral (such as anti-HIV 2 and anti-H 5 N 1 3 ), antifungal, 4 and antimalarial 5 activity as well as the inhibition of trypanosome T. brucei activity. 6 (−)-Gossypol is currently in Phase II clinical trials and displays single-agent antitumor activity in patients with advanced malignancies. 7 The removal or mask of aldehyde groups has been shown to significantly reduce the toxicity of gossypol in humans. 8 As such, a variety of gossypol derivatives has been developed, including gossypol lactones, 9 gossypol nitriles, 5 gossypolone, 10 modification of the main structure of naphthalene, 7,11 etc. Among these, gossypol Schiff bases displayed widespread biological activities. The purpose of the introduction of the imine through the aldehyde was to reduce the toxicity of gossypol without a loss in the activity since the hydroxyl group appears to be essential for the activity in many cases. 12 However, from known results, the reported activities of aldehyde derived compounds, including gossypol Schiff bases, decreased dramatically compared with gossypol itself in terms of antitumor activity ( Figure 1A). 12−15 The antitumor activities of gossypol Schiff bases were improved slightly only when the framework of gossypol was changed into gossypolone ( Figure 1B). 15 The effects of the introduced substituents of gossypol Schiff bases on the antitumor activity were still ambiguous. As a matter of fact, an investigation of the mechanism of the gossypol Schiff bases was not pursued in these previous studies. On the other hand, studies have shown that gossypol may inhibit tumor cells by interacting with Bcl-2 family proteins, which are the central regulators of apoptosis (programmed cell-death). 16 The modulation of the antiapoptotic Bcl-2 family (Bcl-2 and ...

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DOCK 6: Combining techniques to model RNA–small molecule complexes

Cited by 664 publications

References 47 publications

Matrix Metalloproteinase-8 Plays a Pivotal Role in Neuroinflammation by Modulating TNF-α Activation

Matrix Metalloproteinase-8 Plays a Pivotal Role in Neuroinflammation by Modulating TNF-α Activation

Thiolactomycin-based β-Ketoacyl-AcpM Synthase A (KasA) Inhibitors

Gossypol with Hydrophobic Linear Esters Exhibits Enhanced Antitumor Activity as an Inhibitor of Antiapoptotic Proteins

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