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Editorial Board Members’ Collection Series: "Enzyme Inhibition"
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Editorial Board Members’ Collection Series: "Enzyme Inhibition"

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

Deadline for manuscript submissions: closed (20 June 2025) | Viewed by 6604

Special Issue Editors

Prof. Dr. Claudiu T. Supuran

grade E-Mail Website
Guest Editor
NEUROFARBA Department, Sezione di Scienze Farmaceutiche, University of Florence, Via Ugo Schiff 6, I-50019 Sesto Fiorentino, FI, Italy
Interests: drug design; metalloenzymes; carbonic anhydrases; anticancer agents; antiinfectives; sulfonamides; coumarins
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Piotr Paneth

E-Mail Website
Guest Editor
Faculty of Chemistry, Institute of Applied Radiation Chemistry, Lodz University of Technology, Lodz, Poland
Interests: isotope effects; mechanisms of chemical and enzymatic reactions; enzyme inhibition; isotopic fractionation; isotope-ratio mass spectrometry; computational chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The human genome only encodes for around 30,000 genes, which is one third of what was previously believed before the first genomes were cloned, and there has been still significant debate surrounding how many of them are druggable. Presently clinically used drugs act on around 400 of these targets pertaining to proteins, nucleic acids, and (more rarely) sugars or lipids, which belong to the human host or various pathogens (bacteria, fungi, protozoans, and other parasites). Around 50% of the known drug targets are enzymes; thus, enzyme inhibition (and, in some cases, activation) constitutes an important field of biomedical research and therapeutic intervention. The present Special Issue will address all research topics connected with enzymes, as well as their inhibition and activation, based on molecular biology, structural chemical biology, drug design, and pharmacological studies in the field. All enzyme classes will be considered as relevant proteins for such research topics, albeit with a preference for those connected to major biomedical problems, i.e., cancer, infectious diseases, drug resistance, obesity, as well as cardiovascular and central nervous system conditions.

Prof. Dr. Claudiu T. Supuran
Prof. Dr. Piotr Paneth
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 inhibition
  • enzyme activators
  • magnesium/calcium-containing enzymes
  • zinc/iron enzymes
  • PROTACs
  • cancer
  • drug resistance
  • antiinfectives

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Published Papers (6 papers)

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Research

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15 pages, 1401 KiB  
Communication
Evaluating the Effectiveness of Tyrosine Kinase Inhibitors on EGFR Mutations In Vitro
by Hanshuang Shao and Alan Wells
Int. J. Mol. Sci. 2025, 26(13), 6157; https://doi.org/10.3390/ijms26136157 - 26 Jun 2025
Viewed by 158
Abstract
Abnormal expressions and genetic mutations of EGFR are broadly involved in the progression of many human solid tumors, which has led to the development of small molecule inhibitors (TKIs). However, patients’ tumors usually develop resistance to targeted therapeutic TKIs after a period of [...] Read more.
Abnormal expressions and genetic mutations of EGFR are broadly involved in the progression of many human solid tumors, which has led to the development of small molecule inhibitors (TKIs). However, patients’ tumors usually develop resistance to targeted therapeutic TKIs after a period of treatment, mostly due to secondary mutations in EGFR. To date, three major and prevalent point mutations in EGFR, including L858R, T790M, and C797S, impact the use of TKIs in non-small cell lung cancer patients. Although at least four generations of TKIs have been designed and developed by targeting these mutations, how each mono, dual, or triple variant responds to clinical TKIs remains largely undeciphered. To fill this gap, we constructed a series of EGFR mutants and assessed their responses to clinical TKIs in vitro. The first-generation TKI, erlotinib, completely blocked the autophosphorylation of WT, L858R, C797S, and C797S/L858R, but only partially, if at all, in EGFR containing the T790M mutation alone or in combination. The third generation, osimertinib, completely abolished the autophosphorylation of WT, T790M, L858R, and T790M/L858R. It also significantly inhibited C797S and C790S/L858R, but had no effect on T790M/C797S or T790M/C797S/L858R. EAI045, as the fourth-generation TKI, almost completely inhibited WT and all mutants in complete growth media, but EGF-mediated phosphorylation of WT, C797S, and C797S/L858R were only partially inhibited in quiescence media, while the other mutants were fully inhibited. Furthermore, the abolishment of the enhanced tolerance to Dox in cells transiently expressing T790M/L858R and T790M/C797S/L858R by EAI045 suggests that their enhanced autophosphorylation is involved in their resistant ability. These findings provide some insights into how patients carrying typical mutations should be correctly and efficiently treated and why patients present side effects (because of non-specific inhibitory effects on cells without EGFR mutations). Full article
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: "Enzyme Inhibition")
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23 pages, 4887 KiB  
Article
JAK2 Inhibition Augments the Anti-Proliferation Effects by AKT and MEK Inhibition in Triple-Negative Breast Cancer Cells
by Kyu Sic You, Tae-Sung Kim, Su Min Back, Jeong-Soo Park, Kangdong Liu, Yeon-Sun Seong, Dong Joon Kim and Yong Weon Yi
Int. J. Mol. Sci. 2025, 26(13), 6139; https://doi.org/10.3390/ijms26136139 - 26 Jun 2025
Viewed by 346
Abstract
Janus kinase 2 (JAK2) inhibitors have gained regulatory approval for treating various human diseases. While the JAK2/signal tranducer and activator of transcription 3 (STAT3) pathway plays a role in tumorigenesis, JAK2/STAT3 inhibitors have shown limited therapeutic efficacy in triple-negative breast cancer (TNBC). In [...] Read more.
Janus kinase 2 (JAK2) inhibitors have gained regulatory approval for treating various human diseases. While the JAK2/signal tranducer and activator of transcription 3 (STAT3) pathway plays a role in tumorigenesis, JAK2/STAT3 inhibitors have shown limited therapeutic efficacy in triple-negative breast cancer (TNBC). In this study, we assessed the antiproliferative effects of clinically approved JAK2 inhibitors in TNBC cell lines (MDA-MB-231 and HS578T) using the MTT assay. Among the four JAK2 inhibitors evaluated (fedratinib, cerdulatinib, peficitinib, and filgotinib), fedratinib significantly inhibited the proliferation of TNBC cells with IC50 values below 2 μM. Fedratinib also demonstrated superior efficacy in inhibiting long-term colony formation compared to other JAK2 inhibitors. Western blot analyses showed that fedratinib uniquely inhibits the phosphoinositide 3-kinase (PI3K)/AKT pathway and moderately affects the MAP kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, in addition to targeting JAK2/STAT3 signaling. Moreover, fedratinib distinctly decreased MYC and cyclin D1 protein levels while inducing poly (ADP-ribose) polymerase (PARP) cleavage and apoptotic cell death more effectively than other JAK2 inhibitors. We next investigated the effects of simultaneously inhibiting JAK2/STAT3 together with the MEK/ERK or PI3K/AKT pathways, as well as the impact of triple pathway inhibition. Notably, combining ceduratinib with either cobimetinib (MEK inhibitor) and ipatasertib (AKT inhibitor) or trametinib (MEK inhibitor) and alpelisib (PI3K inhibitor) mimicked the effects of fedratinib on the cell proliferation, MYC and cyclin D1 suppression, and pro-apoptotic protein induction. These finding suggest that JAK2 inhibition enhances the anticancer effects of concurrent MEK/ERK and PI3K/AKT pathway inhibition, while JAK2 inhibition alone shows minimal efficacy in TNBC cells. Full article
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: "Enzyme Inhibition")
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23 pages, 2412 KiB  
Article
DPPPRED-IV: An Ensembled QSAR-Based Web Server for the Prediction of Dipeptidyl Peptidase 4 Inhibitors
by Laureano E. Carpio, Marta Olivares, Rita Ortega-Vallbona, Eva Serrano-Candelas, Yolanda Sanz and Rafael Gozalbes
Int. J. Mol. Sci. 2025, 26(12), 5579; https://doi.org/10.3390/ijms26125579 - 11 Jun 2025
Viewed by 348
Abstract
Type 2 diabetes mellitus (T2DM) is a complex and prevalent metabolic disorder, and dipeptidyl peptidase 4 (DPP4) inhibitors have proven effective, yet the identification of novel inhibitors remains challenging due to the vastness of chemical space. In this study, we developed DPPPRED-IV, a [...] Read more.
Type 2 diabetes mellitus (T2DM) is a complex and prevalent metabolic disorder, and dipeptidyl peptidase 4 (DPP4) inhibitors have proven effective, yet the identification of novel inhibitors remains challenging due to the vastness of chemical space. In this study, we developed DPPPRED-IV, a web-based ensembled system integrating both binary classification and continuous regression Quantitative Structure Activity Relationships (QSAR) models to predict human DPP4 inhibitory activity. A curated dataset of 4 676 ChEMBL compounds was subjected to genetic algorithm descriptor selection and multiple machine learning algorithms; classification models were combined via a soft voting ensemble, while regression models estimated IC50 values. All models underwent external 10-fold cross-validation and applicability domain analysis. The final models were integrated into a user-friendly web server, allowing predictions from SMILES inputs. Experimental testing of 29 MolPort compounds at 1.5 µM confirmed that 14 predicted actives exhibited significant inhibition, supporting the tool’s performance in early-stage screening. DPPPRED IV is freely available within the ChemoPredictionSuite and offers a resource to accelerate decision making, reduce costs and minimize animal use in T2DM drug discovery. Full article
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: "Enzyme Inhibition")
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16 pages, 4025 KiB  
Article
Leveraging SARS-CoV-2 Main Protease (Mpro) for COVID-19 Mitigation with Selenium-Based Inhibitors
by Viviana De Luca, Andrea Angeli, Alessio Nocentini, Paola Gratteri, Silvia Pratesi, Damiano Tanini, Vincenzo Carginale, Antonella Capperucci, Claudiu T. Supuran and Clemente Capasso
Int. J. Mol. Sci. 2024, 25(2), 971; https://doi.org/10.3390/ijms25020971 - 12 Jan 2024
Cited by 4 | Viewed by 2862
Abstract
The implementation of innovative approaches is crucial in an ongoing endeavor to mitigate the impact of COVID-19 pandemic. The present study examines the strategic application of the SARS-CoV-2 Main Protease (Mpro) as a prospective instrument in the repertoire to combat the [...] Read more.
The implementation of innovative approaches is crucial in an ongoing endeavor to mitigate the impact of COVID-19 pandemic. The present study examines the strategic application of the SARS-CoV-2 Main Protease (Mpro) as a prospective instrument in the repertoire to combat the virus. The cloning, expression, and purification of Mpro, which plays a critical role in the viral life cycle, through heterologous expression in Escherichia coli in a completely soluble form produced an active enzyme. The hydrolysis of a specific substrate peptide comprising a six-amino-acid sequence (TSAVLQ) linked to a p-nitroaniline (pNA) fragment together with the use of a fluorogenic substrate allowed us to determine effective inhibitors incorporating selenium moieties, such as benzoselenoates and carbamoselenoates. The new inhibitors revealed their potential to proficiently inhibit Mpro with IC50-s in the low micromolar range. Our study contributes to the development of a new class of protease inhibitors targeting Mpro, ultimately strengthening the antiviral arsenal against COVID-19 and possibly, related coronaviruses. Full article
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: "Enzyme Inhibition")
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25 pages, 9282 KiB  
Article
Combined In Silico and In Vitro Analyses to Assess the Anticancer Potential of Thiazolidinedione–Thiosemicarbazone Hybrid Molecules
by Agata Paneth, Barbara Kaproń, Tomasz Plech, Roman Paduch, Nazar Trotsko and Piotr Paneth
Int. J. Mol. Sci. 2023, 24(24), 17521; https://doi.org/10.3390/ijms242417521 - 15 Dec 2023
Cited by 7 | Viewed by 1893
Abstract
The number of people affected by cancer and antibiotic-resistant bacterial infections has increased, such that both diseases are already seen as current and future leading causes of death globally. To address this issue, based on a combined in silico and in vitro approach, [...] Read more.
The number of people affected by cancer and antibiotic-resistant bacterial infections has increased, such that both diseases are already seen as current and future leading causes of death globally. To address this issue, based on a combined in silico and in vitro approach, we explored the anticancer potential of known antibacterials with a thiazolidinedione–thiosemicarbazone (TZD–TSC) core structure. A cytotoxicity assessment showed encouraging results for compounds 2–4, with IC50 values against T98G and HepG2 cells in the low micromolar range. TZD–TSC 3 proved to be most toxic to cancer cell lines, with IC50 values of 2.97 ± 0.39 µM against human hepatoma HepG2 cells and IC50 values of 28.34 ± 2.21 µM against human glioblastoma T98G cells. Additionally, compound 3 induced apoptosis and showed no specific hemolytic activity. Furthermore, treatment using 3 on cancer cell lines alters these cells’ morphology and further suppresses migratory activity. Molecular docking, in turn, suggests that 3 would have the capacity to simultaneously target HDACs and PPARγ, by the activation of PPARγ and the inhibition of both HDAC4 and HDAC8. Thus, the promising preliminary results obtained with TZD–TSC 3 represent an encouraging starting point for the rational design of novel chemotherapeutics with dual antibacterial and anticancer activities. Full article
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: "Enzyme Inhibition")
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Review

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17 pages, 463 KiB  
Review
PDE9A Promotes Calcium-Handling Dysfunction in Right Heart Failure via cGMP–PKG Pathway Suppression: A Mechanistic and Therapeutic Review
by Spencer Thatcher, Arbab Khalid, Abu-Bakr Ahmed, Randeep Gill and Ali Kia
Int. J. Mol. Sci. 2025, 26(13), 6361; https://doi.org/10.3390/ijms26136361 - 1 Jul 2025
Viewed by 193
Abstract
Right heart failure (RHF) is a major cause of morbidity and mortality, often resulting from pulmonary arterial hypertension and characterized by impaired calcium (Ca2+) handling and maladaptive remodeling. Phosphodiesterase 9A (PDE9A), a cGMP-specific phosphodiesterase, has been proposed as a potential contributor [...] Read more.
Right heart failure (RHF) is a major cause of morbidity and mortality, often resulting from pulmonary arterial hypertension and characterized by impaired calcium (Ca2+) handling and maladaptive remodeling. Phosphodiesterase 9A (PDE9A), a cGMP-specific phosphodiesterase, has been proposed as a potential contributor to RHF pathogenesis by suppressing the cardioprotective cGMP–PKG signaling pathway—a conclusion largely extrapolated from left-sided heart failure models. This review examines existing evidence regarding PDE9A’s role in RHF, focusing on its effects on intracellular calcium cycling, fibrosis, hypertrophy, and contractile dysfunction. Data from preclinical models demonstrate that pathological stress upregulates PDE9A expression in cardiomyocytes, leading to diminished PKG activation, impaired SERCA2a function, RyR2 instability, and increased arrhythmogenic Ca2+ leak. Pharmacological or genetic inhibition of PDE9A restores cGMP signaling, improves calcium handling, attenuates hypertrophic and fibrotic remodeling, and enhances ventricular compliance. Early-phase clinical studies in heart failure populations suggest that PDE9A inhibitors are well tolerated and effectively augment cGMP levels, although dedicated trials in RHF are still needed. Overall, these findings indicate that targeting PDE9A may represent a promising therapeutic strategy to improve outcomes in RHF by directly addressing the molecular mechanisms underlying calcium mishandling and myocardial remodeling. Full article
(This article belongs to the Special Issue Editorial Board Members’ Collection Series: "Enzyme Inhibition")
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