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Enzyme Inhibitors in Drug Discovery and Development
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Enzyme Inhibitors in Drug Discovery and Development

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Biochemistry and Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 6212

Special Issue Editors

Dr. Francesco Balestri

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Guest Editor
1. Biochemistry Unit, Department of Biology, University of Pisa, 56123 Pisa, Italy
2. Interdepartmental Research Center Nutrafood “Nutraceuticals and Food for Health”, University of Pisa, 56124 Pisa, Italy
Interests: enzyme kinetics; protein purification; enzyme modulatiom; drug discovery; metabolite extraction
Special Issues, Collections and Topics in MDPI journals
Dr. Roberta Moschini

E-Mail Website
Guest Editor
Department of Biology, University of Pisa, Via S. Zeno 51, 56127 Pisa, Italy
Interests: enzyme kinetic; enzyme inhibition assays; nutraceuticals; natural or synthetic bioactive compounds; proteins purification; oxidative stress; antioxidants; cellular biochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Enzymes are biomolecules required for the anabolic and catabolic pathways in all living organism. However, it is well known that the alteration of the activity of certain enzymes may be involved in the onset of specific human diseases. 

This special issue will include reviews and research articles on the topic "enzyme inhibitors in drug discovery and development" focusing on those enzymes whose activity and expression is considered harmful for human cell function. Reviews included in this special issue will present the state-of-the-art of the in vitro and/or in silico high-efficiency drug screening methods used to identify chemical or natural compounds capable of effectively interacting with enzymatic targets in order to develop a drug suitable for the clinical practice. The research articles will report both the identification of new enzymatic inhibitors potentially useful as drugs and the characterization of the mechanisms of action of new and already known enzyme inhibitors at in vitro or in vivo level. Please send me an abstract prior to submission to make sure that your work falls within the scope of this special issue.

Dr. Francesco Balestri
Dr. Roberta Moschini
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biology is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • enzyme characterization
  • enzyme modulation
  • natural drugs
  • synthetic drugs
  • drug-enzyme modeling interaction
  • drug testing
  • drug development

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Published Papers (3 papers)

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18 pages, 2244 KiB  
Article
The Importance of the “Time Factor” for the Evaluation of Inhibition Mechanisms: The Case of Selected HDAC6 Inhibitors
by Edoardo Cellupica, Gianluca Caprini, Gianluca Fossati, Doris Mirdita, Paola Cordella, Mattia Marchini, Ilaria Rocchio, Giovanni Sandrone, Andrea Stevenazzi, Barbara Vergani, Christian Steinkühler and Maria Antonietta Vanoni
Biology 2023, 12(8), 1049; https://doi.org/10.3390/biology12081049 - 26 Jul 2023
Cited by 2 | Viewed by 1861
Abstract
Histone deacetylases (HDACs) participate with histone acetyltransferases in the modulation of the biological activity of a broad array of proteins, besides histones. Histone deacetylase 6 is unique among HDAC as it contains two catalytic domains, an N-terminal microtubule binding region and a [...] Read more.
Histone deacetylases (HDACs) participate with histone acetyltransferases in the modulation of the biological activity of a broad array of proteins, besides histones. Histone deacetylase 6 is unique among HDAC as it contains two catalytic domains, an N-terminal microtubule binding region and a C-terminal ubiquitin binding domain. Most of its known biological roles are related to its protein lysine deacetylase activity in the cytoplasm. The design of specific inhibitors is the focus of a large number of medicinal chemistry programs in the academy and industry because lowering HDAC6 activity has been demonstrated to be beneficial for the treatment of several diseases, including cancer, and neurological and immunological disorders. Here, we show how re-evaluation of the mechanism of action of selected HDAC6 inhibitors, by monitoring the time-dependence of the onset and relief of the inhibition, revealed instances of slow-binding/slow-release inhibition. The same approach, in conjunction with X-ray crystallography, in silico modeling and mass spectrometry, helped to propose a model of inhibition of HDAC6 by a novel difluoromethyloxadiazole-based compound that was found to be a slow-binding substrate analog of HDAC6, giving rise to a tightly bound, long-lived inhibitory derivative. Full article
(This article belongs to the Special Issue Enzyme Inhibitors in Drug Discovery and Development)
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16 pages, 3052 KiB  
Article
Combination Effects of Integrin-linked Kinase and Abelson Kinase Inhibition on Aberrant Mitosis and Cell Death in Glioblastoma Cells
by Abigail Cunningham, Maddisen Brown, Jonathan Dresselhuis, Nicole Robinson, Keni Hervie, Michael E. Cox and Julia Mills
Biology 2023, 12(7), 906; https://doi.org/10.3390/biology12070906 - 25 Jun 2023
Viewed by 1440
Abstract
In cancer cells, inhibition of integrin-linked kinase (ILK) increases centrosome declustering causing mitotic arrest and cell death. Yet, not all cancer cells are susceptible to anti-ILK treatment alone. We investigate a combination drug strategy targeting ILK and another oncogenic kinase, Abelson kinase (ABL). [...] Read more.
In cancer cells, inhibition of integrin-linked kinase (ILK) increases centrosome declustering causing mitotic arrest and cell death. Yet, not all cancer cells are susceptible to anti-ILK treatment alone. We investigate a combination drug strategy targeting ILK and another oncogenic kinase, Abelson kinase (ABL). Drug-concentration viability assays (i.e., MTT assays) indicate that ILK and ABL inhibitors in combination decreased the viability of glioblastoma cells over the ILK drug QLT-0267 alone. Combination strategies also increased aberrant mitoses and cell death over QLT-0267 alone. This was evident from an increase in mitotic arrest, apoptosis and a sub-G1 peak following FAC analysis. In vitro, ILK and ABL localized to the centrosome and the putative ILK kinase domain was important for this localization. Increased levels of cytosolic ABL are associated with its transformative abilities. ILK inhibitor effects on survival correlated with its ability to decrease cytosolic ABL levels and inhibit ABL’s localization to mitotic centrosomes in glioblastoma cells. ILK inhibitor effects on ABL’s centrosomal localization were reversed by the proteasomal inhibitor MG132 (a drug that inhibits ABL degradation). These results indicate that ILK regulates ABL at mitotic centrosomes and that combination treatments targeting ILK and ABL are more effective then QLT-0267 alone at decreasing the survival of dividing glioblastoma cells. Full article
(This article belongs to the Special Issue Enzyme Inhibitors in Drug Discovery and Development)
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20 pages, 3676 KiB  
Article
Dissecting the Activity of Catechins as Incomplete Aldose Reductase Differential Inhibitors through Kinetic and Computational Approaches
by Francesco Balestri, Giulio Poli, Lucia Piazza, Mario Cappiello, Roberta Moschini, Giovanni Signore, Tiziano Tuccinardi, Umberto Mura and Antonella Del Corso
Biology 2022, 11(9), 1324; https://doi.org/10.3390/biology11091324 - 6 Sep 2022
Cited by 1 | Viewed by 1768
Abstract
The inhibition of aldose reductase is considered as a strategy to counteract the onset of both diabetic complications, upon the block of glucose conversion in the polyol pathway, and inflammation, upon the block of 3-glutathionyl-4-hydroxynonenal reduction. To ameliorate the outcome of aldose reductase [...] Read more.
The inhibition of aldose reductase is considered as a strategy to counteract the onset of both diabetic complications, upon the block of glucose conversion in the polyol pathway, and inflammation, upon the block of 3-glutathionyl-4-hydroxynonenal reduction. To ameliorate the outcome of aldose reductase inhibition, minimizing the interference with the detoxifying role of the enzyme when acting on toxic aldehydes, “differential inhibitors”, i.e., molecules able to inhibit the enzyme depending on the substrate the enzyme is working on, has been proposed. Here we report the characterization of different catechin derivatives as aldose reductase differential inhibitors. The study, conducted through both a kinetic and a computational approach, highlights structural constraints of catechin derivatives relevant in order to affect aldose reductase activity. Gallocatechin gallate and catechin gallate emerged as differential inhibitors of aldose reductase able to preferentially affect aldoses and 3-glutathionyl-4-hydroxynonenal reduction with respect to 4-hydroxynonenal reduction. Moreover, the results highlight how, in the case of aldose reductase, a substrate may affect not only the model of action of an inhibitor, but also the degree of incompleteness of the inhibitory action, thus contributing to differential inhibitory phenomena. Full article
(This article belongs to the Special Issue Enzyme Inhibitors in Drug Discovery and Development)
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