The 1.8-Å crystal structure of a matrix metalloproteinase 8-barbiturate inhibitor complex reveals a previously unobserved mechanism for collagenase substrate recognition.

Brandstetter, Hans; Grams, Frank; Glitz, Dagmar; Lang, Anja; Huber, Robert; Bode, Wolfram; Krell, Hans-Willi; Engh, Richard A.

doi:10.1016/s0021-9258(20)80307-x

Cited by 11 publications

(22 citation statements)

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“…14 At these distances (<2.05 Å), donor-acceptor coordination interactions between Zn 2+ and polar groups of a given protease inhibitor would be possible. 44,45 It should be noted that the superimposed compounds did not always contain groups that could be attributed to all of the pharmacophoric centers shown in Figures 6 and 7. For example, inhibitors 5 and 10 only partially occupied space within the overlaid structures.…”

Section: Resultsmentioning

confidence: 99%

Novel Small-Molecule Inhibitors of Anthrax Lethal Factor Identified by High-Throughput Screening

et al. 2006

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Anthrax lethal factor (LF) is a key virulence factor of anthrax lethal toxin. We screened a chemolibrary of 10,000 drug-like molecules for their ability to inhibit LF and identified 18 novel small molecules with potent LF inhibitory activity. Three additional LF inhibitors were identified through further structure-activity relationship (SAR) analysis. All 21 compounds inhibited LF with an IC50 range of 0.8 to 11 muM, utilizing mixed-mode competitive inhibition. An evaluation of inhibitory activity against a range of unrelated proteases showed relatively high specificity for LF. Furthermore, pharmacophore modeling of these compounds showed a high degree of similarity to the model published by Panchal et al. (Nat. Struct. Mol. Biol. 2004, 11, 67-72), indicating that the conformational features of these inhibitors are structurally compatible with the steric constraints of the substrate-binding pocket. These novel LF inhibitors and the structural scaffolds identified as important for inhibitory activity represent promising leads to pursue for further LF inhibitor development.

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Section: Resultsmentioning

confidence: 99%

Novel Small-Molecule Inhibitors of Anthrax Lethal Factor Identified by High-Throughput Screening

et al. 2006

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“…16 In contrast to the promising in vivo results stated above, micro-PET imaging studies using the potent hydroxamate-based MMPI radiotracer [ 22 Thus, to date no clinical application for imaging MMP activity in vivo is available, and the need of alternative imaging strategies is obvious. This is the aim of the current study which was initiated to investigate pyrimidine-2,4,6-triones [25][26][27]32 as a new class of potential MMPI radiotracer with superior MMP potency, i.e., characterized by IC 50 values in the lower nanomolar range. Although well-known as barbiturates (sedatives, hypnotics, narcotics, and antiepileptic agents), the 5,5disubstituted pyrimidine-2,4,6,-triones presented here exhibit neither toxicity nor sedative effects in CD-1 mice.…”

Section: Discussionmentioning

confidence: 99%

“…Yield: 83% of a viscous brown-red oil. MS (EI): m/e (intensity %): 381 (M + H + , 16), 380 (M + , 100), 379 (M + H + , 16), 378 (M + , 85), 323 (22), 322 (40), 321 (100), 320 (39), 319 (82), 294 (4), 293 (23), 292 (4), 291 (26), 278 (8), 277 (30), 276 (9), 275 (30), 264 (5), 263 (32), 262 (5), 261 (34), 179 (10), 148 (35), 89 (15). Anal.…”

Section: Methods B: Reaction Of [4-(4-hydroxy-phenoxy)-phenyl]-acetic...unclassified

“…25 In contrast to the bidentate zinc(II) binding moiety of the hydroxamates the pyrimidine-2,4,6-triones bindseach as an enolic tautomersin an almost tridentate manner to the zinc(II) active site. 26,27 In the work presented here we suggest the C-5-disubstituted pyrimidine-2,4,6-triones as a new class of potential MMPI radiotracers with improved MMP potency for the molecular imaging of MMPs in vivo by means of the scintigraphic techniques single photon emission computed tomography (SPECT) or positron emission tomography (PET). Compound 10a, 5-[4-(4-bromophenoxy)-phenyl]-5-[4-(2-hydroxyethyl)-piperazin-1-yl]-pyrimidine-2,4,6-trione, was chosen as the lead compound which is a potent non-hydroxamate MMPI with the phenoxyphenyl residue (P 1 ′ substituent) reaching into the narrow S 1 ′ pocket of the MMP and the hydroxyethyl piperazine residue (P 2 ′ substituent) oriented to the S 2 ′ site of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

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C-5-Disubstituted Barbiturates as Potential Molecular Probes for Noninvasive Matrix Metalloproteinase Imaging

et al. 2005

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Studies have demonstrated a positive correlation between inflammation, metastasis, or atherosclerosis and the unbalanced or culminated expression of matrix metalloproteinases (MMPs). The molecular imaging of locally upregulated MMP activity in vivo is a clinical challenge. Actually, radioligands based on nonpeptidyl MMP inhibitors (MMPIs) are currently in development as putative radiopharmaceutical agents for the noninvasive in vivo assessment of activated MMPs. Nonpeptidyl MMPIs bind to the zinc active site of the activated enzyme via mono- (e.g. carboxylate) or bidentate (e.g. hydroxamate) complexation thereby exhibiting a broad-spectrum MMP binding potency. Thus, these mentioned endopeptidase inhibitors should be useable lead compounds for the redevelopment as diagnostic MMPI radiotracers. Recently, the non-hydroxamate C-5-disubstituted pyrimidine-2,4,6-triones were disclosed as subgroup-selective MMP inhibitors. We here describe a set of fine-tuned barbiturates as a new class of MMPI radiotracers for the noninvasive in vivo visualization of activated MMPs using scintigraphic techniques such as SPECT or PET.

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“…Already in 1976, Weinstein et al published a mechanistic model which suggests the existence of a specific histamine tautomer during the interaction with a protein receptor. 16 Furthermore, recent publications such as Brandstetter et al, 8 Pospisil et al, 9 and others [10][11][12][13][14][15] showed that specifically defined tautomeric states of molecules are present and interact with the active-sites residues of target proteins. These results clearly show that in silico screening approaches can only lead to reliable results if all reasonable tautomers including the correct bioactive tautomer form have been processed and have been taken into account during the screening process.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Tautomer Forms on Pharmacophore-Based Virtual Screening

Oellien¹,

Cramer²,

Beyer³

et al. 2006

J. Chem. Inf. Model.

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In the field of in silico screening, many applications do not automatically consider possible tautomeric states of molecules. However, the detection of new compound candidates might rely on correct structural description, which is important for the perfect fit toward the biologically relevant interactions. In this paper, we present a new exhaustive tautomer enumeration approach implemented by means of the CACTVS software package. The approach contains a set of 21 predefined SMIRKS-based transforms and a powerful transformation engine that is capable of generating most tautomers described comprehensively in the literature or found in databases in the field of medicinal chemistry. User-defined tautomer rules applied to specific structural databases or scientific issues can be implemented easily and used instead of the predefined rules. In addition, we describe the impact of tautomer-enriched databases on pharmacophore screening approaches for human matrix metalloproteinase 8 as an example of a protein-based pharmacophore screening scenario and for human cyclin-dependent kinases as an example of a ligand-based pharmacophore screening approach. In both test cases, as a preprocessing step, we have used our new tautomer enumerator tool for the tautomer enrichment of the screening data sets and have used it as a postprocessing step to remove tautomeric duplicates from the results. We could demonstrate that the tautomer-enriched screening data sets show significant advantages compared to their non-enhanced counterparts. The discrimination between hits and nonhits was significantly better in the case of tautomer-enriched databases. Moreover, it has been proved that tautomer-enhanced databases will lead to a higher number of potential hits.

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The 1.8-Å crystal structure of a matrix metalloproteinase 8-barbiturate inhibitor complex reveals a previously unobserved mechanism for collagenase substrate recognition.

Cited by 11 publications

References 0 publications

Novel Small-Molecule Inhibitors of Anthrax Lethal Factor Identified by High-Throughput Screening

Novel Small-Molecule Inhibitors of Anthrax Lethal Factor Identified by High-Throughput Screening

C-5-Disubstituted Barbiturates as Potential Molecular Probes for Noninvasive Matrix Metalloproteinase Imaging

The Impact of Tautomer Forms on Pharmacophore-Based Virtual Screening

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