Current Drug Targets - Volume 20, Issue 15, 2019

Protein kinases play critical roles in the control of cell growth, proliferation, migration, and angiogenesis, through their catalytic activity. Over the past years, numerous protein kinase inhibitors have been identified and are being successfully used clinically. Traditional Chinese medicine (TCM) represents a large class of bioactive substances, and some of them display anticancer activity via inhibiting protein kinases signal pathway. Some of the TCM have been used to treat tumors clinically in China for many years. The p38mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase, serine/threonine-specific protein kinases (PI3K/AKT/mTOR), and extracellular signal-regulated kinases (ERK) pathways are considered important signals in cancer cell development. In the present article, the recent progress of TCM that exhibited significant inhibitory activity towards a range of protein kinases is discussed. The clinical efficacy of TCM with inhibitory effects on protein kinases in treating a tumor is also presented. The article also discussed the prospects and problems in the development of anticancer agents with TCM.

Bromodomain-containing protein 4 (BRD4) belongs to the bromodomain and extraterminal family. BRD4 inhibitors can regulate acetylated lysine and form protein complexes that initiate transcriptional programs as an epigenetic regulator of the histone code. BRD4 was initially considered to be one of the most promising targets for combating malignant tumors. However, many recent studies have shown that BRD4 plays a crucial role in various kinds of diseases, including cancer, coronary heart disease, neurological disorder, and obesity. Currently, several BRD4 inhibitors are undergoing clinical trials. A search for new BRD4 inhibitors appears to be of great utility for developing novel drugs. In this mini-review, we highlight the inhibitors of BRD4 from natural products and synthesized sources, as well as their applications in cancer, glucolipid metabolism, inflammation, neuronal stimulation activation, human immunodeficiency virus and renal fibrosis.

Targeting of therapeutic agents to their specific site of action not only increases the treatment efficacy, but also reduces systemic toxicity. Therefore, various drug delivery systems (DDSs) have been developed to achieve this target. However, most of those DDSs have several issues regarding biocompatibility and environmental hazard. In contrast to the synthetic DDSs, exosome-based natural carriers are biocompatible, biodegradable and safe for the environment. Since exosomes play a role in intercellular communication, they have been widely utilized as carriers for different therapeutic agents. This article was aimed to provide an overview of exosomes as an environment-friendly DDS in terms of engineering, isolation, characterization, application and limitation.

Dengue fever is a disease which is caused by a family of viruses named Flaviviridae which are transmitted by female Aedes mosquitoes. Today, this is endemic in more than 100 nations in the World Health Organization's African, Americas, Eastern Mediterranean, South-East Asia and Western Pacific locales. The treatment of typical dengue is focused on relieving the symptoms and signs. Carica papaya is a very common plant whose leaf extract is used in the treatment of this disease. Despite extensive research on Dengue, not a single vaccine or anti-viral drug was available until 2016 (a partially effective Chimeric Yellow fever virus treated by DENV-Tetravalent Dengue Vaccine for dengue fever made by Sanofi Pasteur). This review highlights dengue fever’s current situation and explains the importance of Natural chemical moieties like methionine–proline anilides, tetrapeptide aldehyde uncovered via Structure Activity Relationship studies. Also, we have reviewed the drug candidates currently in the clinical trials that have the potential to solve these issues. Important patents in the past 20 years have been outlined in this review. An in depth Protein Data Bank analysis of the different possible target proteins that can potentially have a major role in curing Dengue fever has been conducted.

Leptin is an adipocyte-derived hormone product of the obese (ob) gene. Leptin plays an important regulatory role as an immunomodulatory factor in the maintenance and homeostasis of immune functions. Indeed, the role of leptin as an immunomodulator in inflammatory and immune responses has attracted increasing attention in recent years. Leptin mostly affects responses through the immunomodulation of monocytes, dendritic cells, neutrophils, NK cells, and dendritic cells in addition to modulating T and B cell development and functions. Leptin is also an important inflammatory regulator, wherein higher expression influences the secretion rates of IL-6, C-reactive proteins, and TNF-α. Moreover, leptin is highly involved in processes related to human metabolism, inflammatory reactions, cellular development, and diseases, including hematopoiesis. Owing to its diverse immunerelated functions, leptin has been explored as a potential target for therapeutic development in the treatment of autoimmune diseases.

Quinolizidine alkaloids, a main form of alkaloids found in the genus Sophora, have been shown to have many pharmacological effects. This review aims to summarize the photochemical reports and biological activities of quinolizidine alkaloids in Sophora. The collected information suggested that a total of 99 quinolizidine alkaloids were isolated and detected from different parts of Sophora plants, represented by lupinine-type, cytisine-type, sparteine-type, and matrine-type. However, quality control needs to be monitored because it could provide basic information for the reasonable and efficient use of quinolizidine alkaloids as medicines and raw materials. The nonmedicinal parts may be promising to be used as a source of quinolizidine alkaloid raw materials and to reduce the waste of resources and environmental pollution. In addition, the diversity of chemical compounds based on the alkaloid scaffold to make a biological compound library needs to be extended, which may reduce toxicity and find new bioactivities of quinolizidine alkaloids. The bioactivities most reported are in the fields of antitumor activity along with the effects on the cardiovascular system. However, those studies rely on theoretical research, and novel drugs based on quinolizidine alkaloids are expected.

Background: The diazenyl compounds (-N=N- linkage) have been reported to have antimicrobial activity. In modern drug discovery, the drug-receptor interactions are generally explored by the molecular docking studies. Materials and Methods: Three categories of diazenyl scaffolds were screened for the docking studies to explore the binding mechanism of interaction with various microbial targets. The diazenyl Schiff bases (SBN-20, SBN-21, SBN-25, SBN-33, SBN-39, SBN-40 and SBN-42), naphthol pharmacophore based diazenyl Schiff bases (NS-2, NS-8, NS-12, NS-15, NS-21, and NS-23), morpholine based diazenyl chalcones (MD-6, MD-9, MD-14, MD-16, MD-20, and MD-21) were docked against various bacterial and fungal proteins in comparison with different standard drugs. Further, the drug likeliness and ADME properties of these molecules were predicted by QikProp module of the Schrodinger software. Results: Most of the derivatives had shown less docking scores and binding energies towards bacterial proteins, such as dihydropteroate synthase (PDB:2VEG), glucosamine-6-phosphate synthase (PDB:2VF5), dihydrofolate reductase (PDB:3SRW) in comparison with the standard drugs. The naphthol based diazenyl Schiff bases NS-21 and NS-23 were predicted to act on the cytochrome P450 sterol 14-alpha-demethylase (CYP51) (PDB:5FSA) involved in sterol biosynthesis, an essential target for antifungal drugs. The derivative MD-6, NS-2, NS-21, and NS-23 had shown high docking scores against bacterial DNA topoisomerase (PDB:3TTZ) in comparison with the standard drug ciprofloxacin. Further, most of the synthesized derivatives had shown drug like characters. Conclusion: Hence, these compounds can be developed as novel antibacterial agents as potent DNA topoisomerase inhibitors and antifungal agents as CYP51 inhibitors.