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Biomedicines
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New Horizons in Enzyme Inhibitor Discovery: Targets, Design and Evaluation
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New Horizons in Enzyme Inhibitor Discovery: Targets, Design and Evaluation

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: 31 March 2026 | Viewed by 4213

Special Issue Editors

Dr. Chenzhou Hao

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Guest Editor
Department of Neurobiology, Stanford University, Stanford, CA, USA
Interests: structure-based drug design; medicinal chemistry
Dr. Jing Guo

E-Mail Website
Guest Editor
College of Pharmacy, Jinan University, Guangzhou 510632, China
Interests: structure-based drug design; medicinal chemistry
Dr. Yin Sun

E-Mail Website
Guest Editor
Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
Interests: structure-based drug design; medicinal chemistry
Dr. Tongchao Liu

E-Mail Website
Guest Editor
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
Interests: structure-based drug design; medicinal chemistry

Special Issue Information

Dear Colleagues,

We are thrilled to announce the launch of a Special Issue titled “New Horizons in Enzyme Inhibitor Discovery: Targets, Design and Evaluation” and look forward to receiving a range of outstanding contributions that will advance this dynamic field. Enzyme inhibitors represent approximately half of all marketed drugs and have revolutionized human medicine. From the enduring classic aspirin to the newly nirmatrelvir combating the COVID-19 pandemic, as well as from the blockbuster HMG-CoA reductase inhibitors (“-statins”) to the “magic bullet” kinase inhibitors (“-tinibs”), the therapeutic and commercial success of small-molecule enzyme inhibitors has made enzyme targets a central focus of contemporary drug discovery and development. Researchers are showcasing innovative strategies related to the design and development of new enzyme inhibitors, with significant achievements in potential-target validation and new drug discovery. Emerging research methods and paradigms, such as Artificial Intelligence-Driven Drug Discovery (AIDD), open science, and ultra-high-throughput screening, are poised to significantly enhance the discovery of the next generation of enzyme inhibitors. To highlight the latest research and cutting-edge developments in enzyme inhibitor discovery, we are inaugurating this Special Issue. It will feature advancements in various aspects of the field, including but not limited to the design, screening, synthesis, and biological evaluation of novel enzyme inhibitors; pharmacokinetic studies; innovative methodologies; structure–activity and structure–property relationship studies; and the application of structural biology and computational studies for SAR analysis. Contributions to all of the areas outlined above and beyond are welcome. Please ensure that submissions adhere to the current Author Guidelines of Biomedicines.

Dr. Chenzhou Hao
Dr. Jing Guo
Dr. Yin Sun
Dr. Tongchao Liu
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 250 words) can be sent to the Editorial Office for assessment.

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. Biomedicines 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 2600 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 inhibitors
  • drug design
  • inhibitor screening
  • medicinal chemistry
  • targets validation
  • structure–activity relationship
  • structure–property relationship

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Published Papers (5 papers)

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Research

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12 pages, 1730 KB  
Communication
Dual Modulation of Cardiac Ion Pumps: A Small-Molecule SERCA2a SUMOylation Enhancer Also Inhibits the Na+/K+-ATPase
by Carlos Cruz-Cortés, Jaroslava Šeflová and L. Michel Espinoza-Fonseca
Biomedicines 2025, 13(12), 3036; https://doi.org/10.3390/biomedicines13123036 - 10 Dec 2025
Viewed by 241
Abstract
Background: The Na+/K+-ATPase (NKA) maintains electrochemical gradients by exporting Na+ and importing K+ at the expense of ATP hydrolysis. Although NKA inhibition is a well-established strategy for increasing cardiac contractility, existing inhibitors such as cardiotonic steroids (CTS) [...] Read more.
Background: The Na+/K+-ATPase (NKA) maintains electrochemical gradients by exporting Na+ and importing K+ at the expense of ATP hydrolysis. Although NKA inhibition is a well-established strategy for increasing cardiac contractility, existing inhibitors such as cardiotonic steroids (CTS) are limited by serious adverse effects. N106 is a small molecule previously shown to enhance cardiac lusitropy by promoting SERCA2a SUMOylation and, intriguingly, also exerts positive inotropic effects, suggesting additional mechanisms of action. Methods: To test whether N106 directly modulates NKA, we combined ATPase activity assays with molecular docking and microsecond-scale molecular dynamics simulations. Results: Biochemical measurements showed that N106 partially inhibits NKA, achieving ~80% maximal inhibition with an IC50 of 7 ± 1 µM, while leaving the pump’s apparent affinity for Na+, K+, and ATP unchanged. Computational analyses suggest that N106 binds within the canonical CTS-binding pocket but undergoes intermittent unbinding events, consistent with the partial inhibition observed experimentally. Conclusions: These findings identify N106 as a first-in-class dual modulator of cardiac ion pumps, partially inhibiting NKA while previously shown to activate SERCA2a through enhanced SUMOylation. This combined mechanism likely underlies its positive inotropic and lusitropic effects and positions the N106 scaffold as a promising lead for developing next-generation dual-target therapeutics for heart failure. Full article
(This article belongs to the Special Issue New Horizons in Enzyme Inhibitor Discovery: Targets, Design and Evaluation)
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24 pages, 2722 KB  
Article
First Evidence of Anti-Plasmodium vivax (Plasmodiidae): Activity of the Essential Oil and 6-Ishwarone Isolated from Piper alatipetiolatum Yunck. (Piperaceae)
by Glenda Quaresma Ramos, Renata Galvão de Azevedo, André Correa de Oliveira, Maria Luiza Lima da Costa, Felipe Moura Araujo da Silva, Ingrity Suelen Costa Sá, Gisely Cardoso de Melo, Stefanie Costa Pinto Lopes, Gemilson Soares Pontes, Sergio Massayoshi Nunomura, Rita de Cássia Saraiva Nunomura and Rosemary Aparecida Roque
Biomedicines 2025, 13(11), 2785; https://doi.org/10.3390/biomedicines13112785 - 14 Nov 2025
Viewed by 526
Abstract
Background/Objectives: In the Brazilian Amazon, which accounts for over 99% of national malaria cases, 34,260 cases were reported as of August 2025, predominantly caused by Plasmodium vivax, responsible for 86.69% of the infections. The increasing resistance of the parasite to conventional [...] Read more.
Background/Objectives: In the Brazilian Amazon, which accounts for over 99% of national malaria cases, 34,260 cases were reported as of August 2025, predominantly caused by Plasmodium vivax, responsible for 86.69% of the infections. The increasing resistance of the parasite to conventional therapies highlights the urgent need for novel control strategies, with essential oils and plant-derived substances emerging as promising alternatives. Methods: In this context, we evaluated the anti-Plasmodium potential of Piper alatipetiolatum essential oil and its major constituent 6-ishwarone against P. vivax, including cytotoxicity in Vero and PBMCs, molecular docking on dihydrofolate reductase (DHFR) and lactate dehydrogenase (LDH), and in silico pharmacokinetic profiling. Results: Both the oil and 6-ishwarone inhibited P. vivax dose-dependently (2.1 ± 1 to 100%), with IC50 values of 9.25 µg/mL and 3.93 µg/mL, respectively. Importantly, no cytotoxic effects were observed at 24 h, with cell viability ranging from 94.7% to 98.3%, highlighting the selectivity of these compounds towards the parasite over mammalian cells. Docking studies indicated selective binding of 6-ishwarone to DHFR (−7.7 kcal/mol; Ki = 2.27 µM) with key interactions (Trp816, Lys820, Tyr819, Asn823, Thr865), whereas binding to LDH was weaker (−6.2 kcal/mol; Ki = 28.10 µM), suggesting DHFR as the primary molecular target. In silico ADMET predictions and experimental data indicated favorable drug-like properties: TPSA = 20.23 Å2, moderate lipophilicity (LogP = 3.37), soluble (ESOL Log S = −3.58; Ali Log S = −3.89; Silicos-IT Log S = −2.84), high gastrointestinal absorption, BBB permeability (0.985), not a P-glycoprotein substrate (0.11), and low likelihood of CYP inhibition. Toxicity predictions showed non-mutagenic and non-hepatotoxic effects, low cardiotoxicity (hERG inhibition risk 0.08–0.32), low reproductive toxicity (0.03), moderate neurotoxicity (0.28), low acute toxicity (oral LD50 = 2.061 mol/kg), and low chronic toxicity (LOAEL = 1.995 log mg/kg/day). Conclusions: Together, these findings demonstrate that essential oil and 6-ishwarone of P. alatipetiolatum are selective, bioavailable, and promising natural leads for antimalarial drug development. Full article
(This article belongs to the Special Issue New Horizons in Enzyme Inhibitor Discovery: Targets, Design and Evaluation)
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20 pages, 10072 KB  
Article
Design, Synthesis, and Computational Insights into PKMYT1 Inhibitors for the Treatment of Breast Cancer
by Jinyu Yu, Haoyu Zhang, Chuanxu Su, Shizhe Yuan, Nian Liu, Yin Sun, Yixiang Sun, Zixuan Gao, Dongmei Zhao and Maosheng Cheng
Biomedicines 2025, 13(9), 2116; https://doi.org/10.3390/biomedicines13092116 - 29 Aug 2025
Viewed by 963
Abstract
Background: Membrane-associated tyrosine-threonine protein kinase 1 (PKMYT1), which is identified as a synthetic lethal partner of CCNE1, emerged as a promising therapeutic target in oncology. Methods: A series of novel PKMYT1 inhibitors were designed by employing a pharmacophore fusion strategy. [...] Read more.
Background: Membrane-associated tyrosine-threonine protein kinase 1 (PKMYT1), which is identified as a synthetic lethal partner of CCNE1, emerged as a promising therapeutic target in oncology. Methods: A series of novel PKMYT1 inhibitors were designed by employing a pharmacophore fusion strategy. The underlying mechanisms were investigated by means of pharmacological experiments and molecular simulations. Results: Compound MY-14 demonstrated optimal kinase inhibition (IC50 = 0.002 μM) and significant anti-proliferative efficacy against CCNE1-amplified cells (IC50-HCC1569 = 1.06 μM and IC50-OVCAR3 = 0.80 μM). Furthermore, MY-14 induced concentration-dependent apoptosis, inhibited colony formation, and effectively arrested cell-cycle progression at the S-phase through synthetic lethality. Molecular dynamics simulations, Hirshfeld surface analysis, dynamic cross-correlation matrix (DCCM), and MM/GBSA calculations elucidated the molecular mechanism underlying MY-14’s interaction with PKMYT1. Conclusions: MY-14 emerged as a promising compound for the development of a novel PKMYT1 inhibitor. Full article
(This article belongs to the Special Issue New Horizons in Enzyme Inhibitor Discovery: Targets, Design and Evaluation)
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Review

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33 pages, 2706 KB  
Review
Targeting Cathepsins in Neurodegeneration: Biochemical Advances
by Francesca Di Matteo, Mariapia Vietri, Simone D’Alessio, Tania Ciaglia, Erica Federica Vestuto, Giacomo Pepe, Ornella Moltedo, Veronica Di Sarno, Simona Musella, Carmine Ostacolo, Fabio Cominelli, Pietro Campiglia, Alessia Bertamino, Maria Rosaria Miranda and Vincenzo Vestuto
Biomedicines 2025, 13(12), 3019; https://doi.org/10.3390/biomedicines13123019 - 9 Dec 2025
Viewed by 317
Abstract
Background/Objectives: Cathepsins, lysosomal proteases crucial for neuronal proteostasis, mediate the clearance of misfolded and aggregated proteins. Their dysregulation is implicated in neurodegenerative and neuropsychiatric disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. These conditions are characterized by toxic protein accumulation and impaired [...] Read more.
Background/Objectives: Cathepsins, lysosomal proteases crucial for neuronal proteostasis, mediate the clearance of misfolded and aggregated proteins. Their dysregulation is implicated in neurodegenerative and neuropsychiatric disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. These conditions are characterized by toxic protein accumulation and impaired clearance, which exacerbate cellular stress responses, including the unfolded protein response (UPR), oxidative damage, and mitochondrial dysfunction. This review aims to summarize current knowledge on cathepsin roles in these pathways and assess their therapeutic potential. Methods: A comprehensive literature review was conducted, focusing on recent in vitro and in vivo studies investigating cathepsin function, inhibition, and modulation. Mechanistic insights and pharmacological approaches targeting cathepsins were analyzed, with attention to challenges in translating preclinical findings to clinical settings. Results: Cathepsins demonstrate a dual role: their proteolytic activity supports neuronal health by degrading toxic aggregates, but altered or insufficient activity may worsen proteotoxic stress. Studies reveal that cathepsins regulate autophagy, apoptosis, and neuroinflammation both intracellularly and extracellularly. Despite promising mechanistic data, clinical translation is hindered by issues such as poor inhibitor selectivity, limited brain penetration, and variability across preclinical models. Conclusions: Targeting cathepsins presents a promising strategy for treating neurodegenerative and neuropsychiatric disorders, but significant challenges remain. Future research should focus on improving drug specificity and delivery, and on developing standardized models to better predict clinical outcomes. Full article
(This article belongs to the Special Issue New Horizons in Enzyme Inhibitor Discovery: Targets, Design and Evaluation)
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Other

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12 pages, 1727 KB  
Viewpoint
An Overview of Glutaminyl Cyclase as a Promising Drug Target for Alzheimer’s Disease
by Rasajna Madhusudhana, Emily Boyle and Yana Cen
Biomedicines 2025, 13(6), 1467; https://doi.org/10.3390/biomedicines13061467 - 13 Jun 2025
Viewed by 1247
Abstract
Alzheimer’s disease (AD) has become an increasingly pressing concern for the aging population. Current AD treatments mainly focus on cognitive and neuropsychiatric symptoms—with few FDA-approved treatments targeting disease progression itself. The amyloid cascade hypothesis describes the formation and accumulation of β-amyloid (Aβ) oligomers [...] Read more.
Alzheimer’s disease (AD) has become an increasingly pressing concern for the aging population. Current AD treatments mainly focus on cognitive and neuropsychiatric symptoms—with few FDA-approved treatments targeting disease progression itself. The amyloid cascade hypothesis describes the formation and accumulation of β-amyloid (Aβ) oligomers and plaques as a primary event in AD pathogenesis. This hypothesis has served as the foundation of disease-modifying treatment development over the last decade. Recently, glutaminyl cyclase (QC) has been identified as a potential drug target in the amyloid cascade. QC catalyzes the cyclization of Aβ to form pyroglutamated Aβ (pEAβ). pEAβ acts as the seed for the formation of Aβ plaques, thus preventing the formation of pEAβ via QC inhibition, and offers a promising therapeutic strategy against AD. Here, we offer an overview of the pathway QCI research has followed—from the initial testing of imidazole-based inhibitor scaffolds to QCI structural optimization via pharmacophore identification, Varoglutamstat entering clinical trials, and further avenues of bettering specificity and potency for future QCI development. Full article
(This article belongs to the Special Issue New Horizons in Enzyme Inhibitor Discovery: Targets, Design and Evaluation)
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