Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies

Ammazzalorso, Alessandra; Filippis, Barbara De; Campestre, Cristina; Laghezza, Antonio; Marrone, Alessandro; Amoroso, Rosa; Tortorella, Paolo; Agamennone, Mariangela

doi:10.3390/ijms17101768

Cited by 11 publications

(9 citation statements)

References 60 publications

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“…To investigate the BMMPI-binding mechanism, molecular-docking studies were performed on the MMP-2, MMP-8, MMP-9, and MMP-13 catalytic sites. 3D structures used for this study were selected through crossdocking studies, as previously reported [32]. Water molecules surrounding the bisphosphonic function in the experimental structures were maintained in the docking simulations in order to allow for water-mediated interactions of the zinc-binding group with the protein [33].…”

Section: Resultsmentioning

confidence: 99%

Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy

et al. 2020

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Matrix metalloproteinases (MMPs) are a family of enzymes involved at different stages of cancer progression and metastasis. We previously identified a novel class of bisphosphonic inhibitors, selective for MMPs crucial for bone remodeling, such as MMP-2. Due to the increasing relevance of specific MMPs at various stages of tumor malignancy, we focused on improving potency towards certain isoforms. Here, we tackled MMP-9 because of its confirmed role in tumor invasion, metastasis, angiogenesis, and immuno-response, making it an ideal target for cancer therapy. Using a computational analysis, we designed and characterized potent MMP-2/MMP-9 inhibitors. This is a promising approach to develop and clinically translate inhibitors that could be used in combination with standard care therapy for the treatment of skeletal malignancies.

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Section: Resultsmentioning

confidence: 99%

Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy

et al. 2020

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“…Twenty compounds were selected for purchase and the subsequent enzymatic assay. The selected compounds were not similar to the published non-zinc binding MMP-2 inhibitors [28][29][30][31][32].…”

Section: Visual Inspection and Final Selection Of The Hits For Purchasementioning

confidence: 86%

Identification of Non-Zinc Binding Inhibitors of MMP-2 Through Virtual Screening and Subsequent Rescoring

Shamsara

2018

Drug Res (Stuttg)

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MMP-2 belongs to a large family of proteases called matrix metalloproteinases (MMPs) that degrades type IV collagen, the main structural component of basement membranes and gelatin. The main pathologic role of MMP-2 overexpression is to contribute to the development of cancer through the progression of metastasis and angiogenesis. A structure-based virtual screening was employed to find new inhibitors with possible selectivity for MMP-2. The inhibitory activities of 3 inhibitors (one was not a suitable drug-like hit) among 19 purchased compounds were approved by enzyme inhibition assay. 5 hits were non-zinc-binding inhibitors of MMP-2. The results demonstrated that a computer-aided drug design could be successfully applied for discovering new MMP-2 inhibitors. We found inhibitors with new scaffolds for the inhibition of MMP-2 with some selectivity features that could be used for future lead optimization processes. According to the docked pose and MD simulation, compound 13 was expected to interact with the S1' specificity loop of MMP-2 and had 2 π-π interactions and a stable hydrogen bond with the MMP-2 active site. The key feature of compound 13 could be used to guide the design of new non-zinc-binding inhibitors of MMP-2.

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“…Currently, ~500 papers investigating the role of MMP inhibition in myocardial ischemia are available from the last 2 decades in PubMed database. There are several papers that describe the non-zinc binding, allosteric (e.g., π-π stacking) interactions of MMP-2 with selected inhibitors (Di Pizio et al, 2013 ; Agamennone et al, 2016 ; Ammazzalorso et al, 2016 ; Adhikari et al, 2018 ). Most of these papers employ MMP-2 as a potential biomarker for ischemic heart diseases or as a therapeutic target to evoke cardioprotection.…”

Section: Discussionmentioning

confidence: 99%

Development of Matrix Metalloproteinase-2 Inhibitors for Cardioprotection

et al. 2018

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The objective of our present study is to develop novel inhibitors for MMP-2 for acute cardioprotection. In a series of pilot studies, novel substituted carboxylic acid derivatives were synthesized based on imidazole and thiazole scaffolds and then tested in a screeening cascade for MMP inhibition. We found that the MMP-inhibiting effects of imidazole and thiazole carboxylic acid-based compounds are superior in efficacy in comparison to the conventional hydroxamic acid derivatives of the same molecules. Based on these results, a 568-membered focused library of imidazole and thiazole compounds was generated in silico and then the library members were docked to the 3D model of MMP-2 followed by an in vitro medium throughput screening (MTS) based on a fluorescent assay employing MMP-2 catalytic domain. Altogether 45 compounds showed a docking score of >70, from which 30 compounds were successfully synthesized. Based on the MMP-2 inhibitory tests using gelatin zymography, 7 compounds were then selected and tested in neonatal rat cardiac myocytes subjected to simulated I/R injury. Six compounds showed significant cardio-cytoprotecion and the most effective compound (MMPI-1154) significantly decreased infarct size when applied at 1 μM in an ex vivo model for acute myocardial infarction. This is the first demonstration that imidazole and thiazole carboxylic acid-based compounds are more efficacious MMP-2 inhibitor than their hydroxamic acid derivatives. MMPI-1154 is a promising novel cardio-cytoprotective imidazole-carboxylic acid MMP-2 inhibitor lead candidate for the treatment of acute myocardial infarction.

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Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies

Cited by 11 publications

References 60 publications

Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy

Bone-Seeking Matrix Metalloproteinase Inhibitors for the Treatment of Skeletal Malignancy

Identification of Non-Zinc Binding Inhibitors of MMP-2 Through Virtual Screening and Subsequent Rescoring

Development of Matrix Metalloproteinase-2 Inhibitors for Cardioprotection

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