Potent “Clicked” MMP2 Inhibitors: Synthesis, Molecular Modeling and Biological Exploration

Zapico, José María; Serra, Pilar; Garcı́a-Sanmartı́n, Josune; Filipiak, Kamila; Carbajo, Rodrigo J.; Schott, Anne K.; Pineda‐Lucena, Antonio; Martı́nez, Alfredo; Martín‐Santamaría, Sonsoles; Pascual‐Teresa, Beatriz de; Ramos, Ana

doi:10.1039/c0ob00852d

Cited by 30 publications

(27 citation statements)

References 55 publications

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“…Protein ligand structural information is crucial to optimize an initial fragment with weak affinity to a highly potent lead compound. There are some recent examples in the literature where molecular docking provided reasonable SAR to guide further fragment optimization [158][159][160][161]. One example is the study by Barelier et al [159] where they screened a library of 200 fragments against human peroxiredoxin 5 protein using STD NMR and WaterLOGSY experiments.…”

Section: Screening Of Fragment Libraries By Computational Methodsmentioning

confidence: 97%

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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Section: Screening Of Fragment Libraries By Computational Methodsmentioning

confidence: 97%

Fragment Based Drug Design: From Experimental to Computational Approaches

Kumar

Voet²,

Zhang

2012

CMC

151

102

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“…Molecular docking study MMP-2, a zinc-containing enzyme, plays an important role in cancer, by stimulating tumors growth, angiogenesisand metastasis, through its involvement in the degradation of extracellular matrix (Zapico et al, 2011) MMP-2 has been considered for many years an important target for the design of anticancer agents. For the coumarin derivatives 4, 5, 8, 12, 13 and 14 we first evaluated the suitability of these compounds to act as MMP-2 inhibitors by means of docking technique.…”

Section: Biological Activity Resultsmentioning

confidence: 99%

Synthesis and molecular docking of novel non-cytotoxic anti-angiogenic sulfonyl coumarin derivatives against hepatocellular carcinoma cells in vitro

2017

J App Pharma Sci

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Resistance to conventional cytotoxic therapeutics, emphasize the need for efforts to develop non-cytotoxic targeted molecular therapies directed against the pathways involved in the angiogenesis. In this work a new series of coumarin derivatives was synthesized starting from 2-oxo-2H-coumarin-6-sulfonyl chloride (1), 6-nitro-2-oxo-2H-coumarin-3-sulfonyl chloride (10) and 6-amino coumarin-2-one (19). The tested compounds 4, 5, 8, 12, 13 and 14 were non-cytotoxic against hepatocellular carcinoma cells (HepG2) using MMT. These noncytotoxic compounds were evaluated as anti-angiogenic agent. Results revealed that compounds 8 and 12 exhibited MMP-independent anti-migratory activity, while compounds 4, 5, 8, 13 and 14 induced MMPdependent anti-migratory activity against hepatocellular carcinoma. Therefore, these coumarin molecules can be utilized as lead compounds to develop potential non-toxic angiogenesis inhibitors and small molecular ligands to target (HepG2). Compound 4 considered a promising anti-angiogenic agent, where it exhibited MMP-dependent anti-migratory activity and down regulated CD105. Furthermore, the molecular docking of the tested compounds was carried out in order to investigate their binding pattern with the prospective target, MMP -2 (PDB-code: 1HOV). The docking results indicate that all tested compounds exhibited better docking score and good fitting inside the active side of MMP-2 (PDB-code: 1HOV) which was in concomitant with biological results.

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“…Some of these compounds (B184 and B185) have shown IC 50 values in the low nanomolar range against MMP-2, and a promising selectivity profile [113].…”

Section: And Piperidine/tetrahydropyransulfonesmentioning

confidence: 99%

MMP-2 Selectivity in Hydroxamate-Type Inhibitors

Serra

Bruczko²,

Zapico³

et al. 2012

CMC

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Extracellular matrix metalloproteinases (MMPs) are a family of zinc-dependent neutral endopeptidases involved in physiological and pathological processes, through the cleavage of extracellular matrix. MMPs are capable of degrading essentially all matrix components, which is crucial for malignant tumor growth, invasion, metastasis and angiogenesis. The vertebrates MMP family includes at least 26 enzymes (23 have been known in humans) with only MMP-1, 2, and 7 experimentally validated as targets for antitumoral drug design. However, inhibition of MMP-1 has been hypothesized to be the cause of the clinically observed musculoskeletal syndrome when broad spectrum inhibitors are used. On the other hand, MMP-9 is a tricky enzyme, since its inhibition might be useful in treating patients with early-stage cancers, but MMP-9 is an anti-target in patients with advanced disease. So, MMP-9 inhibition should also be prevented. Therefore, selective MMP-2 inhibition arises as a pursued profile for MMP binders. Among them, hydroxamates have been extensively studied as small molecule drug candidates characterized by an effective zinc-binding group plus additional side chains responsible for the selectivity. This article pays particular attention to MMP-2 selectivity on hydroxamate-type inhibitors, especially against MMP-9, and their chemical structure, SAR, general synthetic methods, and molecular modelling studies are here reviewed in order to inspire further design of new effective anticancer agents.

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Potent “Clicked” MMP2 Inhibitors: Synthesis, Molecular Modeling and Biological Exploration

Cited by 30 publications

References 55 publications

Fragment Based Drug Design: From Experimental to Computational Approaches

Fragment Based Drug Design: From Experimental to Computational Approaches

Synthesis and molecular docking of novel non-cytotoxic anti-angiogenic sulfonyl coumarin derivatives against hepatocellular carcinoma cells in vitro

MMP-2 Selectivity in Hydroxamate-Type Inhibitors

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