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New Insight: Enzymes as Targets for Drug Development, 2nd Edition
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New Insight: Enzymes as Targets for Drug Development, 2nd Edition

A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Biochemistry, Molecular and Cellular Biology".

Deadline for manuscript submissions: 28 February 2025 | Viewed by 4758

Special Issue Editor

Prof. Dr. Sung-Kun (Sean) Kim

E-Mail Website
Guest Editor
Department of Natural Sciences, Northeastern State University, Broken Arrow, OK 74014, USA
Interests: biochemistry; enzymology; drug discovery; SELEX (systematic evolution of ligands by exponential enrichment); in vitro selection technique
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In the pharmaceutical community, the most attractive targets for drug development are enzymes. The characterization of enzymes is critical in understanding their reactions. Many analytical methods are needed to completely characterize them, such as purification; kinetics; protein stabilization; optimal pH conditions; temperature; ionic strength; subtract or product binding; ligand/inhibitor/protein interactions; three-dimensional structure; and conformational changes. Recently, in silico analysis has been successfully used for enzyme characterization. Molecular docking and molecular dynamics should are also major techniques. This Special Issue brings together a large number of intriguing subjects to promote ideas on enzymes as targets for drug development.

The following topics will be included in this Special Issue:

  • The improvement of enzyme purification;
  • The development of novel inhibitors;
  • The investigation of enzyme mechanism;
  • Understanding enzyme conformation changes.

Prof. Dr. Sung-Kun (Sean) Kim
Guest Editor

Manuscript Submission Information

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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. Current Issues in Molecular Biology 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 2200 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 kinetics
  • enzyme–ligand or protein-protein interactions
  • enzyme inhibitions
  • enzyme purifications and optimal conditions
  • enzyme or protein structures
  • enzyme or protein computational analysis

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Published Papers (5 papers)

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Research

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15 pages, 6407 KiB  
Article
Identification of Potential Selective PAK4 Inhibitors Through Shape and Protein Conformation Ensemble Screening and Electrostatic-Surface-Matching Optimization
by Xiaoxuan Zhang, Meile Zhang, Yihao Li and Ping Deng
Curr. Issues Mol. Biol. 2025, 47(1), 29; https://doi.org/10.3390/cimb47010029 - 6 Jan 2025
Viewed by 521
Abstract
P21-activated kinase 4 (PAK4) plays a crucial role in the proliferation and metastasis of various cancers. However, developing selective PAK4 inhibitors remains challenging due to the high homology within the PAK family. Therefore, developing highly selective PAK4 inhibitors is critical to overcoming the [...] Read more.
P21-activated kinase 4 (PAK4) plays a crucial role in the proliferation and metastasis of various cancers. However, developing selective PAK4 inhibitors remains challenging due to the high homology within the PAK family. Therefore, developing highly selective PAK4 inhibitors is critical to overcoming the limitations of existing inhibitors. We analyzed the structural differences in the binding pockets of PAK1 and PAK4 by combining cross-docking and molecular dynamics simulations to identify key binding regions and unique structural features of PAK4. We then performed screening using shape and protein conformation ensembles, followed by a re-evaluation of the docking results with deep-learning-driven GNINA to identify the candidate molecule, STOCK7S-56165. Based on this, we applied a fragment-replacement strategy under electrostatic-surface-matching conditions to obtain Compd 26. This optimization significantly improved electrostatic interactions and reduced binding energy, highlighting its potential for selectivity. Our findings provide a novel approach for developing selective PAK4 inhibitors and lay the theoretical foundation for future anticancer drug design. Full article
(This article belongs to the Special Issue New Insight: Enzymes as Targets for Drug Development, 2nd Edition)
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27 pages, 8937 KiB  
Article
Using Multiscale Molecular Modeling to Analyze Possible NS2b-NS3 Protease Inhibitors from Philippine Medicinal Plants
by Allen Mathew Fortuno Cordero and Arthur A. Gonzales III
Curr. Issues Mol. Biol. 2024, 46(7), 7592-7618; https://doi.org/10.3390/cimb46070451 - 18 Jul 2024
Viewed by 1525
Abstract
Within the field of Philippine folkloric medicine, the utilization of indigenous plants like Euphorbia hirta (tawa-tawa), Carica papaya (papaya), and Psidium guajava (guava) as potential dengue remedies has gained attention. Yet, limited research exists on their comprehensive [...] Read more.
Within the field of Philippine folkloric medicine, the utilization of indigenous plants like Euphorbia hirta (tawa-tawa), Carica papaya (papaya), and Psidium guajava (guava) as potential dengue remedies has gained attention. Yet, limited research exists on their comprehensive effects, particularly their anti-dengue activity. This study screened 2944 phytochemicals from various Philippine plants for anti-dengue activity. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiling provided 1265 compounds demonstrating pharmacokinetic profiles suitable for human use. Molecular docking targeting the dengue virus NS2b-NS3 protease’s catalytic triad (Asp 75, Ser 135, and His 51) identified ten ligands with higher docking scores than reference compounds idelalisib and nintedanib. Molecular dynamics simulations confirmed the stability of eight of these ligand–protease complexes. Molecular Mechanics/Poisson–Boltzmann Surface Area (MM/PBSA) analysis highlighted six ligands, including veramiline (−80.682 kJ/mol), cyclobranol (−70.943 kJ/mol), chlorogenin (−63.279 kJ/mol), 25beta-Hydroxyverazine (−61.951 kJ/mol), etiolin (−59.923 kJ/mol), and ecliptalbine (−56.932 kJ/mol) with favorable binding energies, high oral bioavailability, and drug-like properties. This integration of traditional medical knowledge with advanced computational drug discovery methods paves new pathways for the development of treatments for dengue. Full article
(This article belongs to the Special Issue New Insight: Enzymes as Targets for Drug Development, 2nd Edition)
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16 pages, 4901 KiB  
Article
Dual Inhibition of PI3 Kinase and MAP Kinase Signaling Pathways in Intrahepatic Cholangiocellular Carcinoma Cell Lines Leads to Proliferation Arrest but Not Apoptosis
by Jessica Schüler, Martina Vockerodt, Niloofar Salehzadeh, Jürgen Becker and Jörg Wilting
Curr. Issues Mol. Biol. 2024, 46(7), 7395-7410; https://doi.org/10.3390/cimb46070439 - 13 Jul 2024
Viewed by 1141
Abstract
Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly, intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly [...] Read more.
Cholangiocellular carcinoma (CCA) is the second most common primary liver cancer, with increasing incidence worldwide and inadequate therapeutic options. Intra- and extrahepatic bile ducts have distinctly different embryonic origins and developmental behavior, and accordingly, intra- and extrahepatic CCAs (ICC vs. ECC) are molecularly different. A promising strategy in oncotherapy is targeted therapy, targeting proteins that regulate cell survival and proliferation, such as the MAPK/ERK and PI3K/AKT/mTOR signaling pathways. Inhibitors of these pathways have been tested previously in CCA cell lines. However, these cell lines could not be clearly assigned to ICC or ECC, and the results indicated apoptosis induction by targeted therapeutics. We tested targeted therapeutics (selumetinib, MK2206) in three defined ICC cell lines (HuH28, RBE, SSP25). We observed additive effects of the dual inhibition of the two pathways, in accordance with the inhibition of phospho-AKT and phospho-ERK1/2 expression. Proliferation was blocked more effectively with dual inhibition than with each single inhibition, but cell numbers did not drop below baseline. Accordingly, we observed G1 phase arrest but not apoptosis or cell death (measured by cleaved caspase-3, AIFM1 regulation, sub-G0/G1 phase). We conclude that the dual inhibition of the MAPK/ERK and PI3K/AKT/mTOR pathways is highly effective to block the proliferation of ICC cell lines in vitro; however, potential clinical applications must be critically examined, as a proliferation block could also induce resistance to standard therapies. Full article
(This article belongs to the Special Issue New Insight: Enzymes as Targets for Drug Development, 2nd Edition)
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Review

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17 pages, 1192 KiB  
Review
Significance of Malic Enzyme 1 in Cancer: A Review
by Rina Fujiwara-Tani, Chie Nakashima, Hitoshi Ohmori, Kiyomu Fujii, Yi Luo, Takamitsu Sasaki, Ruiko Ogata and Hiroki Kuniyasu
Curr. Issues Mol. Biol. 2025, 47(2), 83; https://doi.org/10.3390/cimb47020083 - 29 Jan 2025
Viewed by 366
Abstract
Malic enzyme 1 (ME1) plays a key role in promoting malignant phenotypes in various types of cancer. ME1 promotes epithelial–mesenchymal transition (EMT) and enhances stemness via glutaminolysis, energy metabolism reprogramming from oxidative phosphorylation to glycolysis. As a result, ME1 promotes the malignant phenotypes [...] Read more.
Malic enzyme 1 (ME1) plays a key role in promoting malignant phenotypes in various types of cancer. ME1 promotes epithelial–mesenchymal transition (EMT) and enhances stemness via glutaminolysis, energy metabolism reprogramming from oxidative phosphorylation to glycolysis. As a result, ME1 promotes the malignant phenotypes of cancer cells and poor patient prognosis. In particular, ME1 expression is promoted in hypoxic environments associated with hypoxia-inducible factor (HIF1) α. ME1 is overexpressed in budding cells at the cancer invasive front, promoting cancer invasion and metastasis. ME1 also generates nicotinamide adenine dinucleotide (NADPH), which, together with glucose-6-phosphate dehydrogenase (G6PD) and isocitrate dehydrogenase (IDH1), expands the NADPH pool, maintaining the redox balance in cancer cells, suppressing cell death by neutralizing mitochondrial reactive oxygen species (ROS), and promoting stemness. This review summarizes the latest research insights into the mechanisms by which ME1 contributes to cancer progression. Because ME1 is involved in various aspects of cancer and promotes many of its malignant phenotypes, it is expected that ME1 will become a novel drug target in the near future. Full article
(This article belongs to the Special Issue New Insight: Enzymes as Targets for Drug Development, 2nd Edition)
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18 pages, 2252 KiB  
Review
The Strong Inhibition of Pancreatic Lipase by Selected Indonesian Medicinal Plants as Anti-Obesity Agents
by Min Rahminiwati, Dyah Iswantini, Trivadila, Rut Novalia Rahmawati Sianipar, Rani Melati Sukma, Susi Indariani and Anggia Murni
Curr. Issues Mol. Biol. 2025, 47(1), 39; https://doi.org/10.3390/cimb47010039 - 9 Jan 2025
Viewed by 571
Abstract
Obesity is characterized by the accumulation of excessive fat, potentially leading to degenerative diseases. Pancreatic lipase, an enzyme responsible for converting 50–70% of dietary fat into monoglycerides, free fatty acids, and various other smaller molecules, plays a crucial role in fat metabolism. Therefore, [...] Read more.
Obesity is characterized by the accumulation of excessive fat, potentially leading to degenerative diseases. Pancreatic lipase, an enzyme responsible for converting 50–70% of dietary fat into monoglycerides, free fatty acids, and various other smaller molecules, plays a crucial role in fat metabolism. Therefore, this study aimed to review selected Indonesian medicinal plants with the potential to inhibit the activity of the pancreatic lipase enzyme. The results showed that kunci pepet (Kaempferiae angustifolia Rosc.), asam gelugur (Garcinia atroviridis), temulawak (Curcuma xanthorrhiza), jombang (Taraxacum officinale F. H. Wigg), pegagan (Centella asiatica), and pala (Myristica fragrans) had strong inhibitory effects, exceeding 50% for both in vitro and in vivo studies. Therefore, further studies are needed to explore the potential of these medicinal plants as anti-obesity treatments. Full article
(This article belongs to the Special Issue New Insight: Enzymes as Targets for Drug Development, 2nd Edition)
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