Fragment-Based Discovery of Indole Inhibitors of Matrix Metalloproteinase-13

Taylor, Steven J.; Abeywardane, Asitha; Liang, Shuang; Muegge, Ingo; Padyana, Anil K.; Xiong, Zhaoming; Hill-Drzewi, Melissa; Farmer, Bennett T.; Li, Xiang; Collins, Brandon; Li, John Xiang; Heim-Riether, Alexander; Proudfoot, John; Zhang, Qiang; Goldberg, Daniel R.; Zuvela-Jelaska, Ljiljana; Zaher, Hani; Li, Jun; Farrow, Neil A.

doi:10.1021/jm201129m

Cited by 39 publications

(41 citation statements)

References 35 publications

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“…7 Non zinc-chelating inhibitors have been reported for MMP-8, 85 MMP-12 [86][87][88] and MMP-13 [89][90][91][92][93][94][95][96][97][98][99] . The enthusiasm for non zinc-chelating inhibitors started with the discovery of compound 29 at Sanofi laboratories.…”

Section: Positive Impactmentioning

confidence: 99%

Targeting Matrix Metalloproteinases: Exploring the Dynamics of the S1′ Pocket in the Design of Selective, Small Molecule Inhibitors

2014

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Matrix metalloproteinases (MMPs) are important targets for pathological conditions such as arthritis, chronic obstructive pulmonary disease, and cancer. The failure of the first broad-spectrum MMP inhibitors in clinical trials has led researchers to address the selectivity as one of their main objectives. The S1' pocket has been widely used to modulate the selectivity of these enzymes because it displays the highest variability in length and shape among MMPs. In this review, we encourage medicinal chemists to also consider the dynamics of this pocket as an important parameter to achieve the desired selectivity. To support this proposal, we collect examples from the literature where the flexibility of the S1' pocket was highlighted as a relevant and significant issue affecting selectivity. We also review the experimental studies on the dynamics of this pocket.

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Section: Positive Impactmentioning

confidence: 99%

Targeting Matrix Metalloproteinases: Exploring the Dynamics of the S1′ Pocket in the Design of Selective, Small Molecule Inhibitors

2014

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“…We cannot cover all of these studies and a number of recently published reviews can be consulted [10,13,15,21,101,102]. Recent studies that utilized fragment growing as an optimization strategy include the discovery of Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) [70], Acetylcholine-binding protein (AChBP) [103], Matrix metalloproteinases (MMPs) [104] and phosphatidylinositol-3 kinases (PI3Ks) [88] inhibitors. In one of these studies, Cheng et al [70] screened a library of 4000 fragments against BACE1, using SPR and identified 2-aminoquinoline as initial fragment hit.…”

Section: Fragment Growingmentioning

confidence: 99%

“…An overview of some of the recent successes is presented in ( Table 3) that includes work by Taylor et al [104] who carried out virtual screening of an in-house library to identify fragment hits that can bind S1' pocket of MMP-13, a member of MMPs with apparent role in rheumatoid arthritis. The high scoring hits from virtual screening were enriched with some diverse scaffolds to prepare a library of approximately 1000 fragments that was further characterized using biochemical screening, STD NMR, size exclusion chromatography and mass spectrometry.…”

Section: Recent Success In Computational Fragment Screeningmentioning

confidence: 99%

Fragment Based Drug Design: From Experimental to Computational Approaches

Kumar

Voet²,

Zhang

2012

CMC

151

102

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Fragment based drug design has emerged as an effective alternative to high throughput screening for the identification of lead compounds in drug discovery in the past fifteen years. Fragment based screening and optimization methods have achieved credible success in many drug discovery projects with one approved drug and many more compounds in clinical trials. The fragment based drug design starts with the identification of fragments or low molecular weight compounds that generally bind with weak affinity to the target of interest. The fragments that form high quality interactions are then optimized to lead compounds with high affinity and selectivity. The weak affinity of fragments for their target requires the use of biophysical techniques such as nuclear magnetic resonance, X-ray crystallography or surface plasmon resonance to identify hits. These techniques are very sensitive and some of them provide detailed protein fragment interaction information that is important for fragment to lead optimization. Despite the huge advances in technology in the past years, experimental methods of fragment screening suffer several challenges such as low throughput, high cost of instruments and experiments, high protein and fragment concentration requirements. To address challenges posed by experimental screening approaches, computational methods were developed that play an important role in fragment library design, fragment screening and optimization of initial fragment hits. The computational approaches of fragment screening and optimization are most useful when they are used in combination with experimental approaches. The use of virtual fragment based screening in combination with experimental methods has fostered the application of fragment based drug design to important biological targets including protein-protein interactions and membrane proteins such as GPCRs. This review provides an overview of experimental and computational screening approaches used in fragment based drug discovery with an emphasis on recent successes achieved in discovering potent lead molecules using these approaches.

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“…We have found only some rare examples of cross-coupling reactions involving indoles bearing an electron-withdrawing ester group in the 2-position, which indicates that this process has hardly been studied. [17] In the case of model compound 7b, the amide fragment could also be the reason for an additional problem with the reactivity resulting from coordination of a transition metal at this site. Therefore, we decided to investigate this reaction more thoroughly, and screened various catalytic systems {Pd(PPh 3 ) 4 , Pd(dppf) 2 Cl 2 , Pd(dba) 2 + PtBu 3 , Pd(dba) 2 + BINAP, Pd(dba) 2 + Xantphos [dppf = 1,1Ј-bis(diphenylphosphino)ferrocene; dba = dibenzylideneacetone; BINAP = 2,2Ј-bis(diphenylphosphino)-1,1Ј-binaphthyl; Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene]} in the presence of bases (Na 2 CO 3 , K 3 PO 4 ) for the reaction with phenyl boronic acid in various solvents (dioxane/H 2 O, toluene).…”

Section: Introductionmentioning

confidence: 99%

Fischer Reaction with 2‐Perfluoroalkylated Cyclic Imines ― An Efficient Route to 2‐Perfluoroalkyl‐Substituted Tryptamines and Their Derivatives and Homologues

2015

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MALDI mass‐spectrometry measurements are combined with self‐consistent mean‐field (SCF) calculations to detect and predict ligand phase separation on Ag nanoparticles. The experimental and theoretical techniques complement each other by enabling quantification of the nearest‐neighbor distribution of a ligand mixture in a monolayer shell. By tracking a characteristic metallic fragment family, analysis of a MALDI spectrum produces a frequency distribution corresponding to specific ligand patterning. Inherent to the SCF calculation is the enumeration of local interactions that dictate ligand assembly. Interweaving MALDI and SCF facilitates a comparison between the experimentally and theoretically derived frequency distributions as well as their deviation from a well‐mixed state. Thus, we combine these techniques to detect and predict phase separation in monolayers that mix uniformly or experience varying degrees of de‐mixing, including microphase separation and stripe formation. Definition of MALDI removed as this is a commonly recognized technique.

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Fragment-Based Discovery of Indole Inhibitors of Matrix Metalloproteinase-13

Cited by 39 publications

References 35 publications

Targeting Matrix Metalloproteinases: Exploring the Dynamics of the S1′ Pocket in the Design of Selective, Small Molecule Inhibitors

Targeting Matrix Metalloproteinases: Exploring the Dynamics of the S1′ Pocket in the Design of Selective, Small Molecule Inhibitors

Fragment Based Drug Design: From Experimental to Computational Approaches

Fischer Reaction with 2‐Perfluoroalkylated Cyclic Imines ― An Efficient Route to 2‐Perfluoroalkyl‐Substituted Tryptamines and Their Derivatives and Homologues

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