Current Enzyme Inhibition (Volume 22 - Issue 2)

Advances in Structure-Based PARP1 Inhibitors: Implications for Cancer Treatment

2026-05-04

Cancer is characterized by the uncontrolled proliferation of abnormal cells that escape the body's standard regulatory mechanisms. Under normal conditions, cells grow, divide, and die in an orderly manner, but cancerous cells lose this control, growing uncontrollably and invading surrounding tissues. Poly(ADP-ribose) polymerase 1 (PARP1) is a crucial enzyme in this DNA repair process, helping to fix single-strand breaks. PARP inhibitors (PARPi) are a class of drugs that target and block the activity of the PARP1 enzyme, impairing its ability to repair DNA damage. By inhibiting PARP1, these drugs lead to an accumulation of DNA damage in cancer cells, which eventually becomes overwhelming and leads to cell death. This mechanism is particularly effective in cancers with deficiencies in other DNA repair pathways, such as those with BRCA1 and BRCA2 gene mutations. Several PARPi, including Olaparib, Niraparib, and Rucaparib, have been approved by the U.S. Food and Drug Administration (FDA) for use in treating cancers like breast, ovarian, and prostate cancer, particularly in patients with BRCA mutations. The evolution and development of PARP inhibitors have focused on modifying their chemical structure to increase their effectiveness. The design of PARPi also aims to improve their bioavailability, ensuring that the drugs are effectively absorbed into the body and can reach the tumor site in sufficient concentrations. Further developments may also involve combining PARPi with other treatments, such as chemotherapy or immunotherapy, to enhance their overall efficacy.

Enzyme Immobilization: Advancements, Techniques, and Industrial Applications

2026-05-04

The text discusses the critical role of enzyme immobilization in enhancing the efficiency, reusability, and stability of biocatalysts in industrial applications. Immobilization techniques include covalent bonding, encapsulation, adsorption, and cross-linking, each with its unique advantages and challenges. Covalent bonding ensures strong, irreversible attachment of enzymes to supports, preventing leaching and maintaining enzyme stability under various conditions. Encapsulation protects enzymes within a semi-permeable matrix, preserving their activity while allowing access to substrates. Adsorption, relying on weak interactions, is simple and reversible but prone to enzyme leaching. Cross-linking involves intermolecular bonding between enzymes and supports, enhancing stability but potentially altering enzyme conformation. Selecting appropriate supports—organic or inorganic—is crucial to minimize enzyme deactivation and maintain activity. Organic supports, like chitosan and alginate, offer biocompatibility and sustainability, while inorganic supports, such as silica and metal oxides, provide robustness and high surface areas. The text highlights the significance of optimizing immobilization techniques for specific enzymes, considering factors like mechanical resistance, substrate diffusion, and compatibility with enzyme structures. Recent advancements include the development of novel supports like hybrid materials and the application of nanotechnology, which offers enhanced stability and catalytic properties. However, challenges like enzyme deactivation, activity loss over time, and high immobilization costs persist. The text emphasizes ongoing research to address these issues, aiming to improve the economic viability and efficiency of immobilized enzymes in industrial processes. The study underscores the importance of tailoring immobilization strategies to specific enzymes and applications, ensuring maximal catalytic performance and reusability.

Dipeptidyl Peptidase-4 – A Comprehensive Review

2026-05-04

Type 2 diabetes mellitus is a growing global public health issue, with its prevalence projected to increase in the coming decades. It is one of the most prevalent and growing global health concerns, affecting millions of individuals worldwide. The condition is classified into two primary types: Type 1 diabetes, an autoimmune disorder that leads to the destruction of insulin-producing beta cells in the pancreas, and Type 2 diabetes, which is predominantly associated with insulin resistance and inadequate insulin secretion. The various enzymes play a crucial role in the regulation of metabolic pathways, and their dysfunction can contribute to various diseases, including diabetes mellitus. Among these enzymes, the dipeptidyl peptidase-4 serves as a therapeutic target for managing T2D. Inhibiting DPP-4 prevents the breakdown of glucose-dependent insulinotropic peptide and glucagon-like peptide 1, thereby maintaining their natural levels and helping to reduce blood glucose. This review provides a comprehensive overview of the DPP-4 enzyme, including the effects of DPP-4 inhibition on pancreatic beta cell function, skeletal muscle function, and glucose-lowering mechanisms. We believe that this information will aid scientists in developing novel antidiabetic compounds for T2D treatment.

Pharmacognostic, Antioxidant, and Anthelmintic Analysis of Aqueous Extracts from the Aerial Parts of Enhydra fluctuans

2026-05-04

Introduction: Enhydra fluctuans, commonly referred to as water lettuce, is a widely recognized aquatic plant with significant traditional medicinal applications. Its bioactive components have been associated with various pharmacological effects, including antioxidant and anthelmintic properties. This study aimed to assess the potential antioxidant and anthelmintic activities of the aqueous extract of the aerial parts of Enhydra fluctuans.

Methods: Preliminary phytochemical screening was conducted to determine the presence of bioactive constituents such as alkaloids, flavonoids, glycosides, phenolic compounds, carbohydrates, saponins, and tannins. Antioxidant activity was evaluated using the DPPH (2,2-diphenyl-1- picrylhydrazyl) radical scavenging assay, where the IC50 values of the aqueous extract and standard ascorbic acid were compared. The anthelmintic activity was assessed using the earthworm (Eisenia fetida) at three different extract concentrations (25, 50, and 100 mg/ml). Albendazole (10 mg/ml) served as the standard reference, while normal saline acted as the control. Parameters such as time to paralysis and time to death were recorded. Additionally, biochemical and histopathological analyses of the gut were performed to validate the findings.

Results: Phytochemical analysis confirmed the presence of multiple bioactive compounds, supporting the plant's medicinal potential. The aqueous extract exhibited significant antioxidant activity with an IC50 value of 23.29 μg/ml, closely comparable to that of ascorbic acid (27.73 μg/ml). The anthelmintic activity demonstrated a dose-dependent effect, with the 100 mg/ml extract showing a paralysis time of 18 ±1.52 minutes and a death time of 76 ±1.28 minutes. Comparatively, albendazole-treated worms exhibited a paralysis time of 18.32 ±2.64 minutes and a death time of 54.24 ±2.18 minutes. Biochemical and gut histopathological examinations further corroborated the extract's efficacy in anthelmintic activity.

Discussion: These findings highlight the potent antioxidant and anthelmintic properties of the plant's aqueous extract, demonstrating its efficacy comparable to standard drugs. The results support the plant’s therapeutic potential and warrant further investigation into its active constituents and mechanisms of action.

Conclusion: The study confirms the antioxidant and anthelmintic potential of the aqueous extract of Enhydra fluctuans. The significant free radical scavenging activity and dose-dependent anthelmintic effects support its traditional medicinal use. These findings provide a scientific basis for further exploration of Enhydra fluctuans as a natural therapeutic agent, particularly in developing plant-based anthelmintic treatments.

Discovery of SARS-CoV-2 Main Protease Inhibitors from Natural Products via Machine Learning with Pharmacophore Modeling, Similarity Methods, and Molecular Dynamics

2026-05-04

Introduction: The SARS-CoV-2 main protease (Mpro) is a critical enzyme for viral replication, making it an essential target for COVID-19 therapeutic development. In this study, we conducted a comprehensive virtual screening campaign to identify natural product-derived Mpro inhibitors using both structure-based pharmacophore modeling and ligand-based similarity search.

Methods: Two optimized pharmacophore models were constructed from Mpro crystallographic structures (PDB codes 7QBB and 7TIA), validated through ROC analysis, optimized using Dynophores dynamic simulations, and used to screen two natural product libraries. The ligand-based screening was also performed using the co-crystallized ligands of these models, capturing compounds with high shape and atom-based similarity.

Results: Two rounds of molecular docking were performed to filter and refine the hits, leading to the identification of 17 promising compounds with favorable binding interactions and physicochemical profiles. Molecular dynamics simulations of top hits demonstrated stable binding within the Mpro active site, with binding energies supporting their potential as potent inhibitors.

Discussion: The integration of dynamic pharmacophore modeling (dynophore) represents a significant advancement over static models by accounting for protein-ligand interaction flexibility during molecular dynamics. This dynamic approach not only improves hit specificity but also reduces false positives, thereby enhancing the reliability of the virtual screening process. Furthermore, the identification of compound 10313 with high binding stability underscores the predictive value of combining pharmacophore filtering with MD simulations.

Conclusion: This study highlights the value of natural products as a reservoir for Mpro inhibitors, presenting novel candidates for further experimental validation in the fight against COVID-19.

In Vitro Investigation of Acetylcholinesterase Inhibition by Methanolic Extract of Muntingia calabura Bark

2026-05-04

Introduction: The present study aimed at studying the potential of methanolic extract of Muntingia calabura bark (MBE) to inhibit acetylcholinesterase (AChE) in vitro

Methods: Acetylcholinesterase (AChE) activity was assessed using chicken brain homogenate as the enzyme source. The assay was performed using acetylthiocholine iodide as a chromogenic substrate, and the reaction was monitored kinetically at 412 nm by measuring the rate of substrate hydrolysis.

Results: MBE was found to inhibit the AChE activity with an IC50 value of 78.6 ± 2.3 μg/mL. Analysis of the double reciprocal Lineweaver-Burk plot revealed that the rate of substrate hydrolysis by the brain homogenate was characterized by the Km and Vmax values of 93.7 ± 18.8 μM and 0.145±0.009 (delta OD/min at 412nm), respectively. In the presence of the MBE, we observed Km and Vmax values of 76.5 ± 8.9 (without statistical difference compared to the control) and 0.07 ± 0.007 (delta OD/min at 412 nm, statistically lower than the control), respectively, indicating that the MBE non-competitively inhibits AChE.

Discussion: The data presented herein suggest that MBE inhibits AChE in vitro. Additional experiments are required to establish oral availability, toxicity, and efficacy in vivo.

Conclusion: Our work demonstrates the potential of MBE to inhibit AChE in vitro and suggests that the extract warrants further exploration for molecular characterization and potential usefulness in mitigating pathologies in animal models of Alzheimer’s disease.