Discovery of a nanomolar inhibitor of the human glyoxalase-I enzyme using structure-based poly-pharmacophore modelling and molecular docking

Al-Shar’i, Nizar A.; Al-Balas, Qosay; Al-Waqfi, Rand A; Hassan, Mohammad; Alkhalifa, Amer E.; Ayoub, Nehad M.

doi:10.1007/s10822-019-00226-8

Cited by 18 publications

(14 citation statements)

References 47 publications

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“…Pharmacological inhibition of GLO1 enzymatic activity through employment of small-molecule inhibitors acting as glutathione antagonists has been explored before, and GLO1 is a promising target for the development of investigational therapeutics with anti-oncological and antimicrobial (e.g., Trypanosoma cruzi and Leishmania ) activities [ 8 , 12 , 43 ]. Given the striking phenotypic effects observed by us in malignant cells with genetic GLO1 deletion, it will be interesting to examine whether pharmacological target modulation (i.e., inhibition of enzymatic activity) phenocopies the changes caused by stringent genetic target modulation employing CRISPR/Cas9.…”

Section: Discussionmentioning

confidence: 99%

“…Given the striking phenotypic effects observed by us in malignant cells with genetic GLO1 deletion, it will be interesting to examine whether pharmacological target modulation (i.e., inhibition of enzymatic activity) phenocopies the changes caused by stringent genetic target modulation employing CRISPR/Cas9. Indeed, early studies indicate that GLO1 inhibition may show promise for chemosensitization of cancer cells, as substantiated further by the more recent identification of structure-based, non-glutathione competitive inhibitors with potent apoptogenic activity against cultured cancer cells [ 8 , 12 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Recent interest has focused on the emerging role of methylglyoxal and (R)-S-Lactoylglutathione as cellular oncometabolites, involved in tumorigenesis-associated metabolic reprogramming, redox dysregulation, and epigenetic recoding that occurs as a result of posttranslational adduction targeting specific proteins including histones [ 3 , 4 , 5 , 6 , 7 ]. Further, a role of GLO1 in cancer cell chemoresistance has been demonstrated, and the development of pharmacological and genetic strategies modulating GLO1 for experimental cancer therapy has attracted significant attention [ 8 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo

Jandova

Perer

Hua

et al. 2020

Cancers

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Metabolic reprogramming is a molecular hallmark of cancer. Recently, we have reported the overexpression of glyoxalase 1 (encoded by GLO1), a glutathione-dependent enzyme involved in detoxification of the reactive glycolytic byproduct methylglyoxal, in human malignant melanoma cell culture models and clinical samples. However, the specific role of GLO1 in melanomagenesis remains largely unexplored. Here, using genetic target modulation, we report the identification of GLO1 as a novel molecular determinant of invasion and metastasis in malignant melanoma. First, A375 human malignant melanoma cells with GLO1 deletion (A375-GLO1_KO) were engineered using CRISPR/Cas9, and genetic rescue clones were generated by stable transfection of KO clones employing a CMV-driven GLO1 construct (A375-GLO1_R). After confirming GLO1 target modulation at the mRNA and protein levels (RT-qPCR, immunodetection, enzymatic activity), phenotypic characterization indicated that deletion of GLO1 does not impact proliferative capacity while causing significant sensitization to methylglyoxal-, chemotherapy-, and starvation-induced cytotoxic stress. Employing differential gene expression array analysis (A375-GLO1_KO versus A375-GLO1_WT), pronounced modulation of epithelial mesenchymal transition (EMT)-related genes [upregulated: CDH1, OCLN, IL1RN, PDGFRB, SNAI3; (downregulated): BMP1, CDH2, CTNNB1, FN1, FTH1, FZD7, MELTF, MMP2, MMP9, MYC, PTGS2, SNAI2, TFRC, TWIST1, VIM, WNT5A, ZEB1, and ZEB2 (up to tenfold; p < 0.05)] was observed—all of which are consistent with EMT suppression as a result of GLO1 deletion. Importantly, these expression changes were largely reversed upon genetic rescue employing A375-GLO1_R cells. Differential expression of MMP9 as a function of GLO1 status was further substantiated by enzymatic activity and ELISA analysis; phenotypic assessment revealed the pronounced attenuation of morphological potential, transwell migration, and matrigel 3D-invasion capacity displayed by A375-GLO1_KO cells, reversed again in genetic rescue clones. Strikingly, in a SCID mouse metastasis model, lung tumor burden imposed by A375-GLO1_KO cells was strongly attenuated as compared to A375-GLO1_WT cells. Taken together, these prototype data provide evidence in support of a novel function of GLO1 in melanoma cell invasiveness and metastasis, and ongoing investigations explore the function and therapeutic potential of GLO1 as a novel melanoma target.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo

Jandova

Perer

Hua

et al. 2020

Cancers

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“…Finally, a Zn-binding feature (ZBF) that replaced the HBA mapping the Zn ion in the interaction generation protocol was included. This feature was placed at the tail of the HBA vector pointing to the Zn 2+ ion (2 Å from the Zn atom) as detailed in previous studies [ 37 , 38 ]. The distance between the Zn ion in a metalloprotein and the chelating heteroatom are important for effective chelation.…”

Section: Resultsmentioning

confidence: 99%

Identification of Human Leukotriene A4 Hydrolase Inhibitors Using Structure-Based Pharmacophore Modeling and Molecular Docking

et al. 2020

Self Cite

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Leukotriene B4 (LTB4) is a potent, proinflammatory lipid mediator implicated in the pathologies of an array of inflammatory diseases and cancer. The biosynthesis of LTB4 is regulated by the leukotriene A4 hydrolase (LTA4H). Compounds capable of limiting the formation of LTB4, through selective inhibition of LTA4H, are expected to provide potent anti-inflammatory and anti-cancer agents. The aim of the current study is to obtain potential LTA4H inhibitors using computer-aided drug design. A hybrid 3D structure-based pharmacophore model was generated based on the crystal structure of LTA4H in complex with bestatin. The generated pharmacophore was used in a virtual screen of the Maybridge database. The retrieved hits were extensively filtered, then docked into the active site of the enzyme. Finally, they were consensually scored to yield five hits as potential LTA4H inhibitors. Consequently, the selected hits were purchased and their biological activity assessed in vitro against the epoxide hydrolase activity of LTA4H. The results were very promising, with the most active compound showing 73.6% inhibition of the basal epoxide hydrolase activity of LTA4H. The results from this exploratory study provide valuable information for the design and development of more potent and selective inhibitors.

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“…Our research group has been targeting the GLO-I enzyme for almost a decade where a large number of diverse compounds have been designed, synthesized and screened (6,(9)(10)(11)(12)(13)(14)(15). In this study, we build on our previous work of searching for potent GLO-I inhibitors of which natural flavonoids had demonstrated superior affinity to the GLO-I active site, thus serving as a potent inhibitor for the bioconversion of methylglyoxal and as potential anticancer agents (9,11,12).…”

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confidence: 99%

Ellagic acid: A potent glyoxalase-I inhibitor with a unique scaffold

et al. 2020

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The glyoxalase system, particularly glyoxalase-I (GLO-I), has been approved as a potential target for cancer treatment. In this study, a set of structurally diverse polyphenolic natural compounds were investigated as potential GLO-I inhibitors. Ellagic acid was found, computationally and experimentally, to be the most potent GLO-I inhibitor among the tested compounds which showed an IC50 of 0.71 mmol L−1. Its binding to the GLO-I active site seemed to be mainly driven by ionic interaction via its ionized hydroxyl groups with the central Zn ion and Lys156, along with other numerous hydrogen bonding and hydrophobic interactions. Due to its unique and rigid skeleton, it can be utilized to search for other novel and potent GLO-I inhibitors via computational approaches such as pharmacophore modeling and similarity search methods. Moreover, an inspection of the docked poses of the tested compounds showed that chlorogenic acid and dihydrocaffeic acid could be considered as lead compounds worthy of further optimization.

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Discovery of a nanomolar inhibitor of the human glyoxalase-I enzyme using structure-based poly-pharmacophore modelling and molecular docking

Cited by 18 publications

References 47 publications

Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo

Genetic Target Modulation Employing CRISPR/Cas9 Identifies Glyoxalase 1 as a Novel Molecular Determinant of Invasion and Metastasis in A375 Human Malignant Melanoma Cells In Vitro and In Vivo

Identification of Human Leukotriene A4 Hydrolase Inhibitors Using Structure-Based Pharmacophore Modeling and Molecular Docking

Ellagic acid: A potent glyoxalase-I inhibitor with a unique scaffold

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