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Advances in Enzyme Inhibitors: Mechanisms, Applications, and Future Perspectives
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Advances in Enzyme Inhibitors: Mechanisms, Applications, and Future Perspectives

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

Deadline for manuscript submissions: 30 March 2026 | Viewed by 3525

Special Issue Editors

Dr. Clemente Capasso

E-Mail Website
Guest Editor
Institute of Bioscience and Bioresources (IBBR), National Research Council, Via Pietro Castellino 111, 80131 Napoli, Italy
Interests: protein biochemistry; recombinant protein; heterologous expression; carbonic anhydrase; enzyme and protein purification; enzyme characterization; enzyme thermostability; cold-adapted enzymes
Special Issues, Collections and Topics in MDPI journals
Dr. Valeria Pittalà

E-Mail Website
Guest Editor
Department of Drug and Health Sciences, University of Catania, 95125 Catania, Italy
Interests: Nrf2; heme oxygenase; heme oxygenase-1 modulators; enzyme inhibitors; sigma receptors; serotonergic receptors; design of novel biologically active compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Enzyme inhibitors are of the utmost importance in various domains, such as drug discovery, agriculture, and industrial applications. This Special Issue offers a comprehensive overview of recent advancements in enzyme inhibitors, encompassing their diverse mechanisms, applications, and prospects. For instance, as enzyme inhibition is a vital strategy in drug design and development, particularly for the treatment of diseases like cancer, infectious diseases, and metabolic disorders, this issue highlights innovative approaches to designing and optimizing enzyme inhibitors, such as structure-based drug design, fragment-based drug discovery, and computational methods. Additionally, this Special Issue explores the broad spectrum of enzyme inhibitor applications beyond traditional drug therapy, including their utilization in agriculture and industrial processes to produce fine chemicals, biofuels, and pharmaceutical intermediates. Authors are encouraged to present original research, reviews, and perspectives that showcase the diverse applications and potential of enzyme inhibitors in various fields, as well as the development of novel enzyme targets, innovative drug delivery systems, and strategies to overcome resistance mechanisms.

Led by our Editorial Board Members Dr. Clemente Capasso and Dr. Valeria Pittalà, assisted by our Topical Advisory Panel Member Dr. Paula Pinto (Universidade de Trás-os-Montes e Alto Douro, Portugal), this Special Issue serves as a platform for researchers and experts in the field of enzyme inhibitors to share their latest findings, foster interdisciplinary collaborations, and contribute to the advancement of knowledge in this critical area of science and technology. Potential authors are therefore invited to submit contributions that address any aspect of enzyme inhibition, with an emphasis on innovation, relevance, and impact.

Dr. Clemente Capasso
Dr. Valeria Pittalà
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 inhibitors
  • drug design
  • drug discovery
  • drug therapy
  • resistance mechanisms
  • cancer
  • drug delivery systems
  • biocatalysts
  • enzymes in industrial applications

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Published Papers (4 papers)

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Research

25 pages, 9081 KiB  
Article
New Amidino-Substituted Benzimidazole Derivatives as Human Dipeptidyl Peptidase III Inhibitors: Synthesis, In Vitro Evaluation, QSAR, and Molecular Docking Studies
by Dejan Agić, Maja Karnaš Babić, Marijana Hranjec, Domagoj Šubarić, Zrinka Karačić and Marija Abramić
Int. J. Mol. Sci. 2025, 26(8), 3899; https://doi.org/10.3390/ijms26083899 - 20 Apr 2025
Viewed by 167
Abstract
Dipeptidyl peptidase III (DPP III) is a zinc-dependent enzyme that hydrolyses biologically active peptides by cleaving dipeptides from their amino terminus. While the fundamental role of this metallopeptidase remains incompletely understood, human DPP III (hDPP III) has been linked to several pathophysiological processes [...] Read more.
Dipeptidyl peptidase III (DPP III) is a zinc-dependent enzyme that hydrolyses biologically active peptides by cleaving dipeptides from their amino terminus. While the fundamental role of this metallopeptidase remains incompletely understood, human DPP III (hDPP III) has been linked to several pathophysiological processes relevant to drug development. In this study, thirty-six amidino-substituted benzimidazole derivatives, including seven newly synthesized compounds, were examined for their activity against hDPP III by combining in vitro tests, in silico quantitative structure–activity relationship (QSAR) modelling, and molecular docking approaches. The experiments demonstrate that all compounds display inhibitory activity at a 30 µM concentration. A biochemical assay revealed that 2,2′-bithiophene, 4-trifluoromethylphenyl, 4-(N,N-diethylamino)phenyl, and 2,3,4-trihydroxyphenyl as substituents at position 2 of the benzimidazole core enhance inhibitor potency. Additionally, the type of substituent at positions 5(6) of the benzimidazole core influences enzyme inhibition, with effectiveness ranked as follows: 2-imidazolinyl > unsubstituted amidine > 2-tetrahydropyrimidine. A multiple linear regression QSAR model for hDPP III inhibition was developed using four Dragon descriptors (Rww, Mats3e, BELe4, and nCs), which can explain 82% of the inhibitory activity. Docking analysis of the semi-closed form of hDPP III in a complex with the most potent compounds indicates the structural features of the benzimidazole derivatives important for the binding at the hDPP III active site. Full article
(This article belongs to the Special Issue Advances in Enzyme Inhibitors: Mechanisms, Applications, and Future Perspectives)
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26 pages, 7174 KiB  
Article
Analysis of Protein Inhibitors of Trypsin in Quinoa, Amaranth and Lupine Seeds. Selection and Deep Structure–Function Characterization of the Amaranthus caudatus Species
by Martha Hernández de la Torre, Giovanni Covaleda-Cortés, Laura Montesinos, Daniela Covaleda, Juan C. Ortiz, Jaume Piñol, José M. Bautista, J. Patricio Castillo, David Reverter and Francesc Xavier Avilés
Int. J. Mol. Sci. 2025, 26(3), 1150; https://doi.org/10.3390/ijms26031150 - 28 Jan 2025
Viewed by 840
Abstract
Protease inhibitors are biomolecules with growing biotechnological and biomedical relevance, including those derived from plants. This study investigated strong trypsin inhibitors in quinoa, amaranth, and lupine seeds, plant grains traditionally used in Andean South America. Amaranth seeds displayed the highest trypsin inhibitory activity, [...] Read more.
Protease inhibitors are biomolecules with growing biotechnological and biomedical relevance, including those derived from plants. This study investigated strong trypsin inhibitors in quinoa, amaranth, and lupine seeds, plant grains traditionally used in Andean South America. Amaranth seeds displayed the highest trypsin inhibitory activity, despite having the lowest content of aqueous soluble and thermostable protein material. This activity, directly identified by enzymatic assay, HPLC, intensity-fading mass spectrometry (IF-MS), and MS/MS, was attributed to a single protein of 7889.1 Da, identified as identical in Amaranthus caudatus and A. hybridus, with a Ki of 1.2 nM for the canonical bovine trypsin. This form of the inhibitor, which is highly homogeneous and scalable, was selected, purified, and structurally–functionally characterized due to the high nutritional quality of amaranth seeds as well as its promising agriculture–biotech–biomed applicability. The protein was crystallized in complex with bovine trypsin, and its 3D crystal structure resolved at 2.85 Å, revealing a substrate-like transition state interaction. This verified its classification within the potato I inhibitor family. It also evidenced that the single disulfide bond of the inhibitor constrains its binding loop, which is a key feature. Cell culture assays showed that the inhibitor did not affect the growth of distinct plant microbial pathogen models, including diverse bacteria, fungi, and parasite models, such as Mycoplasma genitalium and Plasmodium falciparum. These findings disfavour the notion that the inhibitor plays an antimicrobial role, favouring its potential as an agricultural insect deterrent and prompting a redirection of its functional research. Full article
(This article belongs to the Special Issue Advances in Enzyme Inhibitors: Mechanisms, Applications, and Future Perspectives)
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16 pages, 5796 KiB  
Article
Synthesis of Pyrazole-Based Inhibitors of the Bacterial Enzyme N-Succinyl-l,l-2,6-Diaminopimelic Acid Desuccinylase (DapE) as Potential Antibiotics
by Thomas DiPuma, Jr., Emma H. Kelley, Teerana Thabthimthong, Alayna Bland, Katherine Konczak, Katherine J. Torma, Thahani S. Habeeb Mohammad, Kenneth W. Olsen and Daniel P. Becker
Int. J. Mol. Sci. 2025, 26(1), 22; https://doi.org/10.3390/ijms26010022 - 24 Dec 2024
Viewed by 681
Abstract
Based on the inhibitory potencies from earlier reported tetrazole thioether analogs, we now describe the synthesis and inhibition of pyrazole-based inhibitors of N-succinyl-l,l-2,6-diaminopimelic acid desuccinylase (DapE) from Haemophilus influenzae (HiDapE). The most potent pyrazole analog 7d [...] Read more.
Based on the inhibitory potencies from earlier reported tetrazole thioether analogs, we now describe the synthesis and inhibition of pyrazole-based inhibitors of N-succinyl-l,l-2,6-diaminopimelic acid desuccinylase (DapE) from Haemophilus influenzae (HiDapE). The most potent pyrazole analog 7d bears an aminopyridine amide with an IC50 of 17.9 ± 8.0 μM, and the single enantiomer of ɑ-methyl analog 7q has an IC50 of 18.8 µM, with potency residing in the (R)-enantiomer. Thermal shift revealed strong stabilization upon binding inhibitor (R)-7q with Tm = 50.2 °C and a Ki of 17.3 ± 2.8 μM. Enzyme kinetic experiments confirm competitive inhibition, and docking reveals key active site interactions. Full article
(This article belongs to the Special Issue Advances in Enzyme Inhibitors: Mechanisms, Applications, and Future Perspectives)
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18 pages, 3156 KiB  
Article
Aminomethylmorpholino Nucleosides as Novel Inhibitors of PARP1 and PARP2: Experimental and Molecular Modeling Analyses of Their Selectivity and Mechanism of Action
by Irina Chernyshova, Inna Vasil’eva, Nina Moor, Nikita Ivanisenko, Mikhail Kutuzov, Tatyana Abramova, Alexandra Zakharenko and Olga Lavrik
Int. J. Mol. Sci. 2024, 25(23), 12526; https://doi.org/10.3390/ijms252312526 - 22 Nov 2024
Viewed by 1192
Abstract
Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2) play a key role in DNA repair. As major sensors of DNA damage, they are activated to produce poly(ADP-ribose). PARP1/PARP2 inhibitors have emerged as effective drugs for the treatment of cancers with BRCA deficiencies. Here, [...] Read more.
Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2) play a key role in DNA repair. As major sensors of DNA damage, they are activated to produce poly(ADP-ribose). PARP1/PARP2 inhibitors have emerged as effective drugs for the treatment of cancers with BRCA deficiencies. Here, we explored aminomethylmorpholino and aminomethylmorpholino glycine nucleosides as inhibitors of PARP1 and PARP2, using different enzymatic assays. The compounds bearing thymine or 5-Br(I)-uracil bases displayed the highest inhibition potency, with all of them being more selective toward PARP1. Interaction of the inhibitors with the NAD+ binding cavity of PARP1 (PARP2) suggested by the mixed-type inhibition was demonstrated by molecular docking and the RoseTTAFold All-Atom AI-model. The best PARP1 inhibitors characterized by the inhibition constants in the range of 12–15 µM potentiate the cytotoxicity of hydrogen peroxide by displaying strong synergism. The inhibitors revealed no impact on PARP1/PARP2 affinity for DNA, while they reduced the dissociation rate of the enzyme–DNA complex upon the autopoly(ADP-ribosyl)ation reaction, thus providing evidence that their mechanism of action for PARP trapping is due primarily to catalytic inhibition. The most active compounds were shown to retain selectivity toward PARP1, despite the reduced inhibition potency in the presence of histone PARylation factor 1 (HPF1) capable of regulating PARP1/PARP2 catalytic activity and ADP-ribosylation reaction specificity. The inhibitors obtained seem to be promising for further research as potential drugs. Full article
(This article belongs to the Special Issue Advances in Enzyme Inhibitors: Mechanisms, Applications, and Future Perspectives)
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