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Enzyme-Inhibitor Interaction as Examples of Molecular Recognition
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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) | Viewed by 57256

Special Issue Editor

Prof. Dr. Claudiu T. Supuran

grade E-Mail Website
Guest Editor
Neurofarba Department, Section of Farmaceutical and Neutraceutical Sciences, University of Florence, Sesto Fiorentino, 50019 Florence, Italy
Interests: drug design; metalloenzymes; carbonic anhydrases; anticancer agents; antiinfectives; sulfonamides; coumarins
Special Issues, Collections and Topics in MDPI journals

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

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Keywords

  • enzyme
  • inhibitor
  • activator
  • molecular recognition
  • X-ray crystallography
  • drug design

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Published Papers (7 papers)

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Research

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9993 KiB  
Article
Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies
by Alessandra Ammazzalorso, Barbara De Filippis, Cristina Campestre, Antonio Laghezza, Alessandro Marrone, Rosa Amoroso, Paolo Tortorella and Mariangela Agamennone
Int. J. Mol. Sci. 2016, 17(10), 1768; https://doi.org/10.3390/ijms17101768 - 22 Oct 2016
Cited by 11 | Viewed by 5474
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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2121 KiB  
Article
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
by Nicolino Pala, Francesca Esposito, Dominga Rogolino, Mauro Carcelli, Vanna Sanna, Michele Palomba, Lieve Naesens, Angela Corona, Nicole Grandi, Enzo Tramontano and Mario Sechi
Int. J. Mol. Sci. 2016, 17(8), 1371; https://doi.org/10.3390/ijms17081371 - 20 Aug 2016
Cited by 12 | Viewed by 8754
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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1977 KiB  
Article
Staphylococcal Superantigen-Like Protein 1 and 5 (SSL1 & SSL5) Limit Neutrophil Chemotaxis and Migration through MMP-Inhibition
by Kirsten J. Koymans, Adinda Bisschop, Mignon M. Vughs, Kok P. M. Van Kessel, Carla J. C. De Haas and Jos A. G. Van Strijp
Int. J. Mol. Sci. 2016, 17(7), 1072; https://doi.org/10.3390/ijms17071072 - 5 Jul 2016
Cited by 28 | Viewed by 6095
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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3364 KiB  
Article
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
by Thomas Fischer and Rainer Riedl
Int. J. Mol. Sci. 2016, 17(3), 314; https://doi.org/10.3390/ijms17030314 - 1 Mar 2016
Cited by 15 | Viewed by 7897
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

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661 KiB  
Review
Modulation of Compartmentalised Cyclic Nucleotide Signalling via Local Inhibition of Phosphodiesterase Activity
by Marcella Brescia and Manuela Zaccolo
Int. J. Mol. Sci. 2016, 17(10), 1672; https://doi.org/10.3390/ijms17101672 - 2 Oct 2016
Cited by 48 | Viewed by 7503
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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8404 KiB  
Review
Non-Classical Inhibition of Carbonic Anhydrase
by Carrie L. Lomelino, Claudiu T. Supuran and Robert McKenna
Int. J. Mol. Sci. 2016, 17(7), 1150; https://doi.org/10.3390/ijms17071150 - 16 Jul 2016
Cited by 100 | Viewed by 7383
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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14637 KiB  
Review
Structure and Functional Diversity of GCN5-Related N-Acetyltransferases (GNAT)
by Abu Iftiaf Md Salah Ud-Din, Alexandra Tikhomirova and Anna Roujeinikova
Int. J. Mol. Sci. 2016, 17(7), 1018; https://doi.org/10.3390/ijms17071018 - 28 Jun 2016
Cited by 127 | Viewed by 12479
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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