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Special Issue "Enzyme-Inhibitor Interaction as Examples of Molecular Recognition"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Recognition".

Deadline for manuscript submissions: closed (31 August 2016)

Special Issue Editor

Guest Editor
Prof. Dr. Claudiu T. Supuran

Neurofarba Department, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Sesto Fiorentino (Florence) 50019, Italy
Website | E-Mail
Phone: +39-055-4573729/3005
Fax: +39-055-4573385
Interests: drug design; metalloenzymes; carbonic anhydrases; anticancer agents; antiinfectives; sulfonamides; coumarins

Special Issue Information

Dear Colleagues,

Interactions between enzymes and their cognate modulators of activity (inhibitors or activators) are highly specific, efficient, and crucial for a range of physiologic/pathologic processes. Many highly-used drugs belong to the class of enzyme inhibitors. Considering such interactions as key examples for molecular recognition processes, IJMS will publish a Special Issue on these topics. Both review and original articles dealing with molecular recognition processes based on enzyme-inhibitor/activator interactions will be considered for this Special Issue. These topics are relevant for drug design campaigns of more specific, efficient and selective drugs, as well as for the understanding of fundamental processes, which intervene in the complex phenomena of molecular recognition processes between macromolecular receptor (i.e., enzymes and small molecules acting as modulators of their activity).

Prof. Dr. Claudiu T. Supuran
Guest Editor

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 papers will be 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. International Journal of Molecular Sciences 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 1800 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
  • inhibitor
  • activator
  • molecular recognition
  • X-ray crystallography
  • drug design

Published Papers (7 papers)

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Research

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Open AccessArticle Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies
Int. J. Mol. Sci. 2016, 17(10), 1768; doi:10.3390/ijms17101768
Received: 29 July 2016 / Revised: 10 October 2016 / Accepted: 14 October 2016 / Published: 22 October 2016
PDF Full-text (9993 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of
[...] Read more.
Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data. Full article
(This article belongs to the Special Issue Enzyme-Inhibitor Interaction as Examples of Molecular Recognition)
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Open AccessArticle Inhibitory Effect of 2,3,5,6-Tetrafluoro-4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide Derivatives on HIV Reverse Transcriptase Associated RNase H Activities
Int. J. Mol. Sci. 2016, 17(8), 1371; doi:10.3390/ijms17081371
Received: 28 June 2016 / Revised: 12 August 2016 / Accepted: 15 August 2016 / Published: 20 August 2016
PDF Full-text (2121 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The HIV-1 ribonuclease H (RNase H) function of the reverse transcriptase (RT) enzyme catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate, and represents a suitable target for drug development. A particularly attractive approach is constituted by the
[...] Read more.
The HIV-1 ribonuclease H (RNase H) function of the reverse transcriptase (RT) enzyme catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate, and represents a suitable target for drug development. A particularly attractive approach is constituted by the interference with the RNase H metal-dependent catalytic activity, which resides in the active site located at the C-terminus p66 subunit of RT. Herein, we report results of an in-house screening campaign that allowed us to identify 4-[4-(aryl)-1H-1,2,3-triazol-1-yl]benzenesulfonamides, prepared by the “click chemistry” approach, as novel potential HIV-1 RNase H inhibitors. Three compounds (9d, 10c, and 10d) demonstrated a selective inhibitory activity against the HIV-1 RNase H enzyme at micromolar concentrations. Drug-likeness, predicted by the calculation of a panel of physicochemical and ADME properties, putative binding modes for the active compounds, assessed by computational molecular docking, as well as a mechanistic hypothesis for this novel chemotype are reported. Full article
(This article belongs to the Special Issue Enzyme-Inhibitor Interaction as Examples of Molecular Recognition)
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Open AccessArticle Staphylococcal Superantigen-Like Protein 1 and 5 (SSL1 & SSL5) Limit Neutrophil Chemotaxis and Migration through MMP-Inhibition
Int. J. Mol. Sci. 2016, 17(7), 1072; doi:10.3390/ijms17071072
Received: 30 May 2016 / Revised: 27 June 2016 / Accepted: 28 June 2016 / Published: 5 July 2016
Cited by 3 | PDF Full-text (1977 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Matrix metalloproteinases (MMPs) are endopeptidases that degrade components of the extracellular matrix, but also modulate inflammation. During bacterial infections, MMPs are important in the recruitment and migration of inflammatory cells. Besides facilitating cell migration by degrading extracellular matrix components, they potentiate the action
[...] Read more.
Matrix metalloproteinases (MMPs) are endopeptidases that degrade components of the extracellular matrix, but also modulate inflammation. During bacterial infections, MMPs are important in the recruitment and migration of inflammatory cells. Besides facilitating cell migration by degrading extracellular matrix components, they potentiate the action of several inflammatory molecules, including cytokines, chemokines, and antimicrobial peptides. Staphylococcus aureus secretes an arsenal of immune evasion molecules that interfere with immune cell functioning and hamper proper immune responses. An earlier study identified staphylococcal superantigen-like protein 5 (SSL5) as an MMP9 inhibitor. Since multiple MMPs are involved in neutrophil recruitment, we set up an in-depth search for additional MMP inhibitors by testing a panel of over 70 secreted staphylococcal proteins on the inhibition of the two main neutrophil MMPs: MMP8 (neutrophil collagenase) and MMP9 (neutrophil gelatinase B). We identified SSL1 and SSL5 as potent inhibitors of both neutrophil MMPs and show that they are actually broad range MMP inhibitors. SSL1 and SSL5 prevent MMP-induced cleavage and potentiation of IL-8 and inhibit the migration of neutrophils through collagen. Thus, through MMP-inhibition, SSL1 and SSL5 interfere with neutrophil activation, chemotaxis, and migration, all vital neutrophil functions in bacterial clearance. Studies on MMP-SSL interactions can have therapeutic potential and SSL based derivatives might prove useful in treatment of cancer and destructive inflammatory diseases. Full article
(This article belongs to the Special Issue Enzyme-Inhibitor Interaction as Examples of Molecular Recognition)
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Open AccessArticle Molecular Recognition of the Catalytic Zinc(II) Ion in MMP-13: Structure-Based Evolution of an Allosteric Inhibitor to Dual Binding Mode Inhibitors with Improved Lipophilic Ligand Efficiencies
Int. J. Mol. Sci. 2016, 17(3), 314; doi:10.3390/ijms17030314
Received: 10 December 2015 / Revised: 2 February 2016 / Accepted: 14 February 2016 / Published: 1 March 2016
Cited by 6 | PDF Full-text (3364 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Matrix metalloproteinases (MMPs) are a class of zinc dependent endopeptidases which play a crucial role in a multitude of severe diseases such as cancer and osteoarthritis. We employed MMP-13 as the target enzyme for the structure-based design and synthesis of inhibitors able to
[...] Read more.
Matrix metalloproteinases (MMPs) are a class of zinc dependent endopeptidases which play a crucial role in a multitude of severe diseases such as cancer and osteoarthritis. We employed MMP-13 as the target enzyme for the structure-based design and synthesis of inhibitors able to recognize the catalytic zinc ion in addition to an allosteric binding site in order to increase the affinity of the ligand. Guided by molecular modeling, we optimized an initial allosteric inhibitor by addition of linker fragments and weak zinc binders for recognition of the catalytic center. Furthermore we improved the lipophilic ligand efficiency (LLE) of the initial inhibitor by adding appropriate zinc binding fragments to lower the clogP values of the inhibitors, while maintaining their potency. All synthesized inhibitors showed elevated affinity compared to the initial hit, also most of the novel inhibitors displayed better LLE. Derivatives with carboxylic acids as the zinc binding fragments turned out to be the most potent inhibitors (compound 3 (ZHAWOC5077): IC50 = 134 nM) whereas acyl sulfonamides showed the best lipophilic ligand efficiencies (compound 18 (ZHAWOC5135): LLE = 2.91). Full article
(This article belongs to the Special Issue Enzyme-Inhibitor Interaction as Examples of Molecular Recognition)
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Review

Jump to: Research

Open AccessReview Modulation of Compartmentalised Cyclic Nucleotide Signalling via Local Inhibition of Phosphodiesterase Activity
Int. J. Mol. Sci. 2016, 17(10), 1672; doi:10.3390/ijms17101672
Received: 15 July 2016 / Revised: 20 September 2016 / Accepted: 23 September 2016 / Published: 2 October 2016
Cited by 11 | PDF Full-text (661 KB) | HTML Full-text | XML Full-text
Abstract
Cyclic nucleotide phosphodiesterases (PDEs) are the only enzymes that degrade the cyclic nucleotides cAMP and cGMP, and play a key role in modulating the amplitude and duration of the signal delivered by these two key intracellular second messengers. Defects in cyclic nucleotide signalling
[...] Read more.
Cyclic nucleotide phosphodiesterases (PDEs) are the only enzymes that degrade the cyclic nucleotides cAMP and cGMP, and play a key role in modulating the amplitude and duration of the signal delivered by these two key intracellular second messengers. Defects in cyclic nucleotide signalling are known to be involved in several pathologies. As a consequence, PDEs have long been recognized as potential drug targets, and they have been the focus of intense research for the development of therapeutic agents. A number of PDE inhibitors are currently available for the treatment of disease, including obstructive pulmonary disease, erectile dysfunction, and heart failure. However, the performance of these drugs is not always satisfactory, due to a lack of PDE-isoform specificity and their consequent adverse side effects. Recent advances in our understanding of compartmentalised cyclic nucleotide signalling and the role of PDEs in local regulation of cAMP and cGMP signals offers the opportunity for the development of novel strategies for therapeutic intervention that may overcome the current limitation of conventional PDE inhibitors. Full article
(This article belongs to the Special Issue Enzyme-Inhibitor Interaction as Examples of Molecular Recognition)
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Open AccessReview Non-Classical Inhibition of Carbonic Anhydrase
Int. J. Mol. Sci. 2016, 17(7), 1150; doi:10.3390/ijms17071150
Received: 31 May 2016 / Revised: 2 July 2016 / Accepted: 7 July 2016 / Published: 16 July 2016
Cited by 12 | PDF Full-text (8404 KB) | HTML Full-text | XML Full-text
Abstract
Specific isoforms from the carbonic anhydrase (CA) family of zinc metalloenzymes have been associated with a variety of diseases. Isoform-specific carbonic anhydrase inhibitors (CAIs) are therefore a major focus of attention for specific disease treatments. Classical CAIs, primarily sulfonamide-based compounds and their bioisosteres,
[...] Read more.
Specific isoforms from the carbonic anhydrase (CA) family of zinc metalloenzymes have been associated with a variety of diseases. Isoform-specific carbonic anhydrase inhibitors (CAIs) are therefore a major focus of attention for specific disease treatments. Classical CAIs, primarily sulfonamide-based compounds and their bioisosteres, are examined as antiglaucoma, antiepileptic, antiobesity, antineuropathic pain and anticancer compounds. However, many sulfonamide compounds inhibit all CA isoforms nonspecifically, diluting drug effectiveness and causing undesired side effects due to off-target inhibition. In addition, a small but significant percentage of the general population cannot be treated with sulfonamide-based compounds due to a sulfa allergy. Therefore, CAIs must be developed that are not only isoform specific, but also non-classical, i.e. not based on sulfonamides, sulfamates, or sulfamides. This review covers the classes of non-classical CAIs and the recent advances in the development of isoform-specific inhibitors based on phenols, polyamines, coumarins and their derivatives. Full article
(This article belongs to the Special Issue Enzyme-Inhibitor Interaction as Examples of Molecular Recognition)
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Open AccessReview Structure and Functional Diversity of GCN5-Related N-Acetyltransferases (GNAT)
Int. J. Mol. Sci. 2016, 17(7), 1018; doi:10.3390/ijms17071018
Received: 30 May 2016 / Revised: 14 June 2016 / Accepted: 20 June 2016 / Published: 28 June 2016
Cited by 3 | PDF Full-text (14637 KB) | HTML Full-text | XML Full-text
Abstract
General control non-repressible 5 (GCN5)-related N-acetyltransferases (GNAT) catalyze the transfer of an acyl moiety from acyl coenzyme A (acyl-CoA) to a diverse group of substrates and are widely distributed in all domains of life. This review of the currently available data acquired
[...] Read more.
General control non-repressible 5 (GCN5)-related N-acetyltransferases (GNAT) catalyze the transfer of an acyl moiety from acyl coenzyme A (acyl-CoA) to a diverse group of substrates and are widely distributed in all domains of life. This review of the currently available data acquired on GNAT enzymes by a combination of structural, mutagenesis and kinetic methods summarizes the key similarities and differences between several distinctly different families within the GNAT superfamily, with an emphasis on the mechanistic insights obtained from the analysis of the complexes with substrates or inhibitors. It discusses the structural basis for the common acetyltransferase mechanism, outlines the factors important for the substrate recognition, and describes the mechanism of action of inhibitors of these enzymes. It is anticipated that understanding of the structural basis behind the reaction and substrate specificity of the enzymes from this superfamily can be exploited in the development of novel therapeutics to treat human diseases and combat emerging multidrug-resistant microbial infections. Full article
(This article belongs to the Special Issue Enzyme-Inhibitor Interaction as Examples of Molecular Recognition)

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