Current Enzyme Inhibition - Volume 16, Issue 3, 2020

Background: Alzheimer's disease (AD) is an unexplained progressive degenerative brain disease; it accounts for 60-70% of dementia cases worldwide, has an estimated global incidence of 24.3 million, and is associated with deterioration of the central nervous system. Acetylcholinesterase (AChE) is an enzyme that catalyzes the breakdown of acetylcholine to acetate and choline. It is also the potential target of most of the clinically used drugs for the treatment of AD. The degeneration of cholinergic neurons and the loss of neural transmission are the main reasons for the decline of cognitive ability in AD patients. Objective: In recent years, the development of targeted drugs in AD has made significant achievements. The global impact of AD continues to grow, and as a result, the focus of disease-modifying therapies remains elusive. The role of treatment is not limited to pharmacology but involves many factors, such as the psychological, social, and economic aspects of the patient and family. AChE is an important target in AD to consider the use of AChE inhibitors in patients with mild to moderate AD, even though the costs are high and no other direct progress has been made. Although there are many AChE inhibitors, there is no selective potent inhibitor for AChE. There is still a need to address human AChE structure, provide key insights into key protein-ligand interactions, and provide the basis for molecular modeling and structure-based drug design. Conclusion: In this review, we briefly introduce the clinical characteristics of AD, the development of crystal structure, and the latest research on AD. In recent years, the development of different strategies for amyloid-β, BACE1, and type-1 interferon receptor alpha-1 has attracted great attention. There is an urgent need to further characterize available instrumental compounds to explore the use of new selectivity and key protein-ligand interactions in AD. In the past few decades, great progress has been made in the treatment of AD, but AD is still one of the world's problems, and the inability to cure AD, indicates that there is an urgent need for new treatments.

Signal transducer and activator of transcription (STAT3) is an important transcription factor capable of mediating or even driving cancer progression through hyperactivation or gain-offunction mutations. It plays a key role in regulating host immune and inflammatory responses and in the pathogenesis of many cancers. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a vital role in tumor growth and metastasis. Hyperactive STAT3 is also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. The classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. In this review, we discuss the functions and the roles of STAT3 signal in various types of cancers.

Aim: To understand the details of the action of fungal lipase and the mechanism for its observed interfacial activation. Background: Fungal lipase, crucial to biotechnology, functions at the lipid - water interface where it undergoes a poorly understood interfacial activation. Biochemical factors influencing its activation and inhibition are also poorly understood. This study provides a basis for its activity and a plausible mechanism for interfacial activation. Objective: To determine the structures of fungal lipase in different crystal forms in complex with their enzymatic reactants and inhibitors. Methods: X-ray crystallography. Results: Thermomyces lanuginosa lipase was visualized in three crystal forms, of space groups H32, P21 and I222 at 1.3 to 1.45 Å resolution. Rhombohedral crystals have one molecule, lacking segment 241 to 252, as an asymmetric unit, with molecules organized as two trimers. Monoclinic crystals’ asymmetric unit is six intact molecules organized as two, nearly identical trimers, each exhibiting an NCS threefold axis. The “lid” helix was consistently closed. Oligomerization into trimers creates an internal hydrophobic cavity where catalysis occurs. In monoclinic and orthorhombic crystals, active site serines were esterified to fatty acids. Lipase had bound within their trimeric, hydrophobic cavities 1,3-diacylglycerols with fatty acid chain lengths of about 18 carbons. Conclusion: Results suggest trimers are likely the active form of the enzyme at the lipid-water interface. Formation of trimers may provide an explanation for “interfacial activation”.

Background: Medicinal plants and their products are gaining global popularity due to their several health benefits. However, the biological activities of the vast majority of medicinal plant species have not been explored yet. In this study, we evaluated the enzyme inhibitory potential of six medicinal plant species involved in digestion, skin-related problems, and neurological problems. Methods: The 80% methanol extracts of leaves of six locally available plants from the Bagmati province of Nepal were analyzed for their flavonoids content, phenolics content, antioxidant activity, and enzymes inhibitory potential. Antioxidant activity was analyzed by the DPPH assay. Alpha-amylase inhibition was carried out by the DNSA method. Lipase, tyrosinase, elastase, acetylcholinesterase, and butyrylcholinesterase inhibitions were analyzed by using p-NPB, L-DOPA, AAAPVN, acetylthiocholine, and butyrylthiocholine as a respective substrate. Results: Among the analyzed plants species, Artocarpus heterophyllus displayed highest α-amylase (IC50=6.28 ± 0.01 μg/mL), lipase (IC50= 475.14 ± 3.17 μg/mL), elastase (IC50= 72.75 ± 3.41 μg/mL) and acetylcholinesterase (IC50= 68.66 ± 1.71 μg/mL) inhibition, whereas, Actinidia deliciosa displayed highest tyrosinase inhibition (IC50=139.87 ± 0.72 μg/mL) and butyrylcholinesterase inhibition (IC50= 18.32 ± 0.44 μg/mL). Furthermore, Jasminum humile showed no inhibitory tendencies against elastase and Lygodium japonicum showed no inhibition towards lipase and elastase at the given concentration range. Conclusion: Our study revealed that A. deliciosa and A. heterophyllus are the potential source of α- amylase, lipase, elastase, acetylcholinesterase, and butyrylcholinesterase inhibitors. Based on our findings, we concluded that the analyzed plant species are of great scientific interest to the pharmaceutical, cosmetics, and food industries.

Introduction: Lung cancer is presumed to be the most notable cause of morbidity and impermanency in human beings caused by uncontrolled cell proliferation of lung tissue which results in abrupt synthesis of DNA. Methods: Prevention of DNA synthesis can show distinctive effect on lung cancer by utilizing Thymidylate synthase (TS), a key rate-limiting enzyme in the DNA synthesis process. However, the available finite aggregate of clinically approved blockers and their corresponding side effects lead to the urgent origination of novel inhibitors. Results and Discussion: In silico approaches (QSAR and molecular docking) have been accomplished to discover new potential inhibitors of TS providing a new strategy to evolve novel thymidylate synthase inhibitors functional in lung cancer. Conclusion: In the present study chemical features of a series of compounds alongside their activities alternating over numerous orders of magnitudes was utilized to generate QSAR models, and these could be further employed to predict the activity of new designed compounds. 3D–QSAR kNNSW based model with decent statistical data having q2 approximately 95% (internal validation) and 80% (external validation) has validated the importance of steric feature. Further docking analysis using D–score and ligand receptor interactions indicated that all the studied compounds are well accommodated in the binding pocket of TS and disparities in the activity are controlled by hydrogen and hydrophobic interactions.

Introduction: Coronaviruses constitute the subfamily Orthocoronavirinae, in the Coronaviridae family. Those viruses are a positive-sense and very long single-stranded RNA viruses. Infection- related to SARS CoV2 was named as a pandemic disease by the World Health Organization on Mars 4, 2020. Aim and Objective: The objective of this work is the identification of potential vaccine targets of SARS CoV2. We aim to provide the potential therapeutic target that can inhibit the spread of virus and identify miRNAs, and reminding proposals to improving the effectiveness of these vaccines. Methods: Several clinical trials have been stated to design the management process against this pathology and the most proposed drugs have been commercialized for other viral pathologies. Thus, no specific therapeutic protocol has been established. Results: Our result showed that the potential molecules may specific region in the viral ARN and exert an inhibitor activity against the viral transcription. Conclusion: We conclude throughout our results that several potential therapeutic targets can act at different stages of the viral life cycle by identifying siRNA interfering with molecules that may inhibit viral replication.

Background: The last step in the production of androgen testosterone from 4-androstene- 3,17-dione (4-dione) in testis involves the 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3). Blocking this microsomal enzyme with an inhibitor would lower the level of testosterone and, consequently, could be an approach for the treatment of androgen-dependent diseases. RM-532-105 was developed as a steroidal inhibitor of 17β-HSD3, but its mechanism of action is not yet known. Objective: To identify potential binding sites of the 17β-HSD3 substrate 4-dione, cofactor NADPH, as well as inhibitor RM-532-105. Methods: Since there is no crystal structure of 17β-HSD3 available, complexed or not with a ligand, a homology model was prepared followed by molecular docking, and enzymatic assay experiments were performed. Results: Transfected LNCaP prostate cancer cells were used as a source of 17β-HSD3 activity for the transformation of 4-dione into testosterone in the presence of varying concentrations of a substrate, a cofactor or an inhibitor. Molecular modeling experiments and enzymatic assays with these cells suggest a competitive action of RM-532-105 with the cofactor and a non-competitive action with the substrate 4-dione. Conclusion: These results allow the selection of one inhibitor orientation in the enzyme binding site, from the two possibilities predicted by the docking experiments, and appear to be in agreement with previous structure-activity relationships.

Background: Gastroesophageal reflux disease (GERD) is a common chronic gastrointestinal disorder in adults that occurs as the stomach contents reflux and come up into the esophagus due to a dysfunction in the lower oesophageal sphincter. One approach commonly used to treat GERD is inhibition of the activity of pepsin enzyme. Carbon nanotubes (CNTs) are nanoparticles of carbon atoms that possess numerous interesting physical and chemical properties. CTNs functionalization expands the range of their properties to make them soluble in biological fluids and to confer the property of carrying drug or biological macromolecules which increase the scope of their applications in biomedical science. Objective: This study aims to utilize CNTs as a pepsin inhibitor and as a new medication for the treatment of GERD. Methods: The pepsin activity before and after the addition of an exact amount of the CNTs to the reaction mixture was measured colorimetrically. Results: The results showed that both Vmax and Km changed after the addition of CNTs to the pepsin solution indicating a mixed inhibition of pepsin activity. This finding pointed to the ability of CNTs to bind with the pepsin molecule and pepsin-protein complex, therefore inhibiting the enzyme activity. Conclusion: The findings also demonstrated a complete inhibition of pepsin activity by CNTs when increasing the ionic strength of the reaction mixture. It can be inferred that using CNTs at a high concentration of NaCl at 37°C is the optimal condition for pepsin inhibition.