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1.
Recent Advances in Glyoxalase-I Inhibition.
Al-Balas, QA, Hassan, MA, Al-Shar'i, NA, Al Jabal, GA, Almaaytah, AM
Mini reviews in medicinal chemistry. 2019;(4):281-291
Abstract
Glyoxalase system is a ubiquitous system in human cells which has been examined thoroughly for its role in different disease conditions. It is composed of Glyoxalase-I (Glo-I) and Glyoxalase- II which perform an essential metabolic process inside the cell by detoxifying endogenous harmful metabolites, mainly methylglyoxal (MG) into non-toxic D-lactic acid. Tumor cells are well-known for their high metabolic rate which results in elevated levels of toxic metabolites. The over-expression of Glo-I in tumor cells makes this enzyme a pivotal target for anticancer drug development. Glo-I is metalloenzyme with two polypeptide chains and encompasses two active sites with an integral zinc atoms at their center. This review aims to highlight the important role of Glo-I in different pathogenic conditions, and more importantly, it provides a thorough discussion of all known human Glo-I inhibitors since its discovery, a hundred years ago, up to date. It embraces the different classes they belong to, their design and chemical structures. We believe this review will help guide the design of novel and potent human Glo-I inhibitors by providing a handy reference for interested researchers in this target.
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2.
Protein Tyrosine Phosphatase 1B Inhibitors: A Novel Therapeutic Strategy for the Management of type 2 Diabetes Mellitus.
Prabhakar, PK, Sivakumar, PM
Current pharmaceutical design. 2019;(23):2526-2539
Abstract
Diabetes is one of the most common endocrine non-communicable metabolic disorders which is mainly caused either due to insufficient insulin or inefficient insulin or both together and is characterized by hyperglycemia. Diabetes emerged as a serious health issue in the industrialized and developing country especially in the Asian pacific region. Out of the two major categories of diabetes mellitus, type 2 diabetes is more prevalent, almost 90 to 95% cases, and the main cause of this is insulin resistance. The main cause of the progression of type 2 diabetes mellitus has been found to be insulin resistance. The type 2 diabetes mellitus may be managed by the change in lifestyle, physical activities, dietary modifications and medications. The major currently available management strategies are sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors, dipeptidyl peptidase-IV inhibitors, and glucagon-like peptide-1 (GLP-1) agonist. Binding of insulin on the extracellular unit of insulin receptor sparks tyrosine kinase of the insulin receptor which induces autophosphorylation. The phosphorylation of the tyrosine is regulated by insulin and leptin molecules. Protein tyrosine phosphatase-1B (PTP1B) works as a negative governor for the insulin signalling pathways, as it dephosphorylates the tyrosine of the insulin receptor and suppresses the insulin signalling cascade. The compounds or molecules which inhibit the negative regulation of PTP1B can have an inductive effect on the insulin pathway and finally help in the management of diabetes mellitus. PTP1B could be an emerging therapeutic strategy for diabetes management. There are a number of clinical and basic research results which suggest that induced expression of PTP1B reduces insulin resistance. In this review, we briefly elaborate and explain the place of PTP1B and its significance in diabetes as well as a recent development in the PTP1B inhibitors as an antidiabetic therapy.
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3.
Mechanistic insights into the enzymatic activity and inhibition of the replicative polymerase exonuclease domain from Mycobacterium tuberculosis.
Nasir, N, Kisker, C
DNA repair. 2019;:17-25
Abstract
DNA replication fidelity maintains low mutation rates in bacteria. The ε-subunit of a replisome generally acts as the main proofreader during replication, using its 3'-5' exonuclease activity to excise misincorporated bases thereby maintaining faithful replication. In Mycobacterium tuberculosis (Mtb), however, the polymerase and histidinol phosphatase (PHP) domain of the DNA polymerase DnaE1 is the primary proofreader. This domain thus maintains low mutation rates during replication and is an attractive target for drug development. Even though the structures of DnaE polymerases are available from various organisms, including Mtb, the mechanism of exonuclease activity remains elusive. In this study, we sought to unravel the mechanism and also to identify scaffolds that can specifically inhibit the exonuclease activity. To gain insight into the mode of action, we also characterized the PHP domain of the Mtb error-prone polymerase DnaE2 which shares a nearly identical active site with DnaE1-PHP. Kinetic and mutational studies allowed us to identify the critical residue involved in catalysis. Combined inhibition and computational studies also revealed a specific mode of inhibition of DnaE1-PHP by nucleoside diphosphates. Thus, this study lays the foundation for the rational design of novel inhibitors which target the Mtb replicative proofreader.
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4.
Small molecules as inhibitors of PCSK9: Current status and future challenges.
Xu, S, Luo, S, Zhu, Z, Xu, J
European journal of medicinal chemistry. 2019;:212-233
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in regulating lipoprotein metabolism by binding to low-density lipoprotein receptors (LDLRs), leading to their degradation. LDL cholesterol (LDL-C) lowering drugs that operate through the inhibition of PCSK9 are being pursued for the management of hypercholesterolemia and reducing its associated atherosclerotic cardiovascular disease (CVD) risk. Two PCSK9-blocking monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved in 2015. However, the high costs of PCSK9 antibody drugs impede their prior authorization practices and reduce their long-term adherence. Given the potential of small-molecule drugs, the development of small-molecule PCSK9 inhibitors has attracted considerable attention. This article provides an overview of the recent development of small-molecule PCSK9 inhibitors disclosed in the literature and patent applications, and different approaches that have been pursued to modulate the functional activity of PCSK9 using small molecules are described. Challenges and potential strategies in developing small-molecule PCSK9 inhibitors are also discussed.
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5.
Targeting the Thioredoxin System as a Strategy for Cancer Therapy.
Bian, M, Fan, R, Zhao, S, Liu, W
Journal of medicinal chemistry. 2019;(16):7309-7321
Abstract
Thioredoxin reductase (TrxR) participates in the regulation of redox reactions in organisms. It works mainly via its substrate molecule, thioredoxin, to maintain the redox balance and regulate signal transduction, which controls cell proliferation, differentiation, death, and other important physiological processes. In recent years, increasing evidence has shown that the overactivation of TrxR is related to the development of tumors. The exploration of TrxR-targeted antitumor drugs has attracted wide attention and is expected to provide new therapies for cancer treatment. In this perspective, we highlight the specific relationship between TrxR and apoptotic signaling pathways. The cytoplasm and mitochondria both contain TrxR, resulting in the activation of apoptosis. TrxR activity influences reactive oxygen species (ROS) and further regulates the inflammatory signaling pathway. In addition, we discuss representative TrxR inhibitors with anticancer activity and analyze the challenges in developing TrxR inhibitors as anticancer drugs.
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6.
Molecular modeling investigation of the potential mechanism for phytochemical-induced skin collagen biosynthesis by inhibition of the protein phosphatase 1 holoenzyme.
Wongrattanakamon, P, Nimmanpipug, P, Sirithunyalug, B, Saenjum, C, Jiranusornkul, S
Molecular and cellular biochemistry. 2019;(1-2):45-56
Abstract
The most prominent feature of UV-induced photoaged skin is decreased type 1 procollagen. Increase of the TGF-β/Smad signaling through inhibition of the TβRI dephosphorylation by the GADD34-PP1c phosphatase complex represents a promising strategy for the increase in type 1 collagen production and prevention of UV-induced skin photoaging. In this study, the molecular docking and dynamics simulations, and pharmacophore modeling method were run to investigate a possible binding site as well as binding modes between apigenin, daidzein, asiaticoside, obovatol, and astragaloside IV and PP1c. Through docking study, the possible binding site for these phytochemicals was predicted as the hydrophobic (PP1-substrate binding) groove. The result indicates that PP1 is the significant target of these compounds. Moreover, the 20,000-ps MD simulations present that the binding locations and modes predicted by the docking have been slightly changed considering that the MD simulations proffer more reliable details upon the protein-ligand recognition. The MM-GBSA binding free energy calculations and pharmacophore modeling rationally identify that the highly hydrophobic surfaces/pockets at close proximity of the catalytic core are the most favorable binding locations of the herbal compounds, and that some experimental facts upon a possible mechanism of increase in collagen biosynthesis can be explained. The present study theoretically offers the reliable binding target of the herbal compounds, and therefore helps to understanding the action mechanism for natural small molecules that enhance collagen production.
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7.
Gentamicin Targets Acid Sphingomyelinase in Cancer: The Case of the Human Gastric Cancer NCI-N87 Cells.
Albi, E, Cataldi, S, Ceccarini, MR, Conte, C, Ferri, I, Fettucciari, K, Patria, FF, Beccari, T, Codini, M
International journal of molecular sciences. 2019;(18)
Abstract
Emerging literature implicates acid sphingomyelinase in tumor sensitivity/resistance to anticancer treatments. Gentamicin is a drug commonly used as an antimicrobial but its serendipity effects have been shown. Even though many evidences on the role of gentamicin in cancer have been reported, its mechanism of action is poorly understood. Here, we explored acid sphingomyelinase as a possible new target of gentamicin in cancer. Since gastric cancer is one of the most common cancers and represents the second cause of death in the world, we performed the study in NCI-N87 gastric cancer cell line. The effect of the drug resulted in the inhibition of cell proliferation, including a reduction of cell number and viability, in the decrease of MIB-1 proliferative index as well as in the upregulation of cyclin-dependent kinase inhibitor 1A and 1B (CDKN1A and CDKN1B), and growth arrest and DNA-damage 45A (GADD45A) genes. The cytotoxicity was apoptotic as shown by FACS analysis. Additionally, gentamicin reduced HER2 protein, indicating a minor tumor aggressiveness. To further define the involvement of sphingomyelin metabolism in the response to the drug, gene and protein expression of acid and neutral sphingomeylinase was analyzed in comparison with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and vitamin D receptor (VDR), molecules involved in cancer. Gentamicin induced a downregulation of PTEN, VDR, and neutral sphingomyelinase and a strong upregulation of acid sphingomyelinase. Of note, we identified the same upregulation of acid sphingomyelinase upon gentamicin treatment in other cancer cells and not in normal cells. These findings provide new insights into acid sphingomyelinase as therapeutic target, reinforcing studies on the potential role of gentamicin in anticancer therapy.
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8.
Plant α-amylase inhibitors and their effect on the utilization of polysaccharides contained in the diet.
Kurhajec, S, Franc, A
Ceska a Slovenska farmacie : casopis Ceske farmaceuticke spolecnosti a Slovenske farmaceuticke spolecnosti. 2019;(4):148-156
Abstract
Development of civilization diseases such as diabetes mellitus, metabolic syndrome or obesity, enforces the increasing effort to find new drugs, especially from natural sources. These include α-amylase inhibitors, which break down polysacharides into simple sugars in the body of a healthy person. As this cleavage affects the level of blood sugar, which is sought to be therapeutically influenced, there is a growing interest in these substances. This review maps the types of amylase inhibitors, including their natural resources.
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9.
Methyltransferase Inhibitors: Competing with, or Exploiting the Bound Cofactor.
Ferreira de Freitas, R, Ivanochko, D, Schapira, M
Molecules (Basel, Switzerland). 2019;(24)
Abstract
Protein methyltransferases (PMTs) are enzymes involved in epigenetic mechanisms, DNA repair, and other cellular machineries critical to cellular identity and function, and are an important target class in chemical biology and drug discovery. Central to the enzymatic reaction is the transfer of a methyl group from the cofactor S-adenosylmethionine (SAM) to a substrate protein. Here we review how the essentiality of SAM for catalysis is exploited by chemical inhibitors. Occupying the cofactor binding pocket to compete with SAM can be hindered by the hydrophilic nature of this site, but structural studies of compounds now in the clinic revealed that inhibitors could either occupy juxtaposed pockets to overlap minimally, but sufficiently with the bound cofactor, or induce large conformational remodeling leading to a more druggable binding site. Rather than competing with the cofactor, other inhibitors compete with the substrate and rely on bound SAM, either to allosterically stabilize the substrate binding site, or for direct SAM-inhibitor interactions.
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10.
Low-density lipoprotein cholesterol lowering for the prevention of cardiovascular outcomes in patients with ischemic stroke.
Ntaios, G, Milionis, H
International journal of stroke : official journal of the International Stroke Society. 2019;(5):476-482
Abstract
BACKGROUND Low-density lipoprotein (LDL) cholesterol has been long associated with the risk for ischemic stroke, myocardial infarction, and cardiovascular death. For more than a decade, the main pharmacological option to prevent stroke and myocardial infarction through LDL-cholesterol lowering was the use of statins. During the recent years, two novel classes of drugs have proven their efficacy and safety to reduce LDL-cholesterol and prevent cardiovascular events in large, well-conducted randomized controlled trials: ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. AIMS The present review summarizes the evidence arising from the latest trials of lipid-lowering treatment for cardiovascular outcomes prevention and discusses their implications for secondary prevention strategies in patients with ischemic stroke. SUMMARY OF REVIEW There is strong evidence which confirms the hypothesis that the lower the LDL-cholesterol, the less frequent the cardiovascular events are and underlines the importance of treating our ischemic stroke patients with intensive statin treatment aiming at low LDL-cholesterol levels. The very low levels of LDL cholesterol seem to be safe, even in the mid/long term but longer follow-up data are needed. Currently there are no tools to reliably predict cardiovascular outcomes in the specific population of ischemic stroke patients. CONCLUSIONS Stroke physicians should aim for low LDL-cholesterol levels by intensive statin treatment in all ischemic stroke patients. For those patients who are at the highest risk for recurrent stroke or another cardiovascular event and have unacceptable LDL-cholesterol levels despite intensive statin treatment, PCSK9 inhibitors should be considered.