Mini Reviews in Medicinal Chemistry - Volume 23, Issue 3, 2023

The selection of a protein structure is an important step for the success of the drug discovery process using structure-based design. Selection of the right crystal structure is critical as multiple crystal structures are available for the same protein in the Protein Data Bank (PDB). In this communication, we have discussed a systematic approach for selecting the right type of protein structure. Selecting crystal structures of TACE, 11β-HSD1, DprE1, and SARS-CoV-2 M^pro enzymes for some case studies have been discussed for illustration.

Dihydroartemisinin (DHA) is a derivative of artemisinin, which firstly showed higher antimalarial activity. Over the years, DHA has also been discovered to exhibit higher anticancer efficacy without adverse side effects. Although some shortcomings have been discovered during biological evaluation (such as poor aqueous solubility, short half-life, and initial burst release effect), several attempts have been developed to overcome these shortcomings. For example, appropriate delivery techniques were used to improve its anticancer efficacy. In this minireview, we focused on summarizing the anticancer mechanisms, anticancer efficacy of free DHA and in combination therapies, hybrids, and nanoparticle formulations, which will provide adequate insights for its clinical use as anticancer agents, and on the design and synthesis of DHA derivatives for the development of anticancer agents.

Melatonin (N-acetyl-5-methoxytryptamine) is a secretory product of the pineal gland. A great number of studies have been investigating the functions of this indoleamine in various diseases. Excessive proliferation, reduction in apoptosis, increased angiogenesis, invasion, and metastasis are all processes associated with cancerous tissues. In several cancer types, melatonin is reported to significantly impact these processes. Although bone cancer is relatively rare, it is a serious disease that often becomes metastatic, leading to an unsatisfactory prognosis. In recent decades, significant advances have been made in the therapeutic strategies for bone cancer. Nevertheless, few changes have occurred to patients’ outcomes or therapeutic methods. Currently used therapeutic strategies including chemotherapy and radiotherapy often show serious side effects. Moreover, therapeutic options are not sufficient in certain cases, such as metastatic forms of the disease. Therefore, there is a need for a more precise definition of the molecular pathways and cellular functions associated with bone cancer to find novel therapeutic approaches. With such advances, the development of new effective therapies for patients with advanced stage or metastatic forms of the disease will be achieved, resulting in an improved prognosis. This review summarizes what is known about the functions of melatonin in osteosarcoma and Ewing’s sarcoma. We explain the underlying mechanisms of action by which melatonin serves as an antitumor agent in bone cancer as well as provide an insight into its synergistic effects with other chemotherapeutic drugs.

Intestinal mucositis is characterized by inflammation and ulceration of the mucosa that affects the gastrointestinal tract and is associated with administering some drugs, such as 5- Fluorouracil (5-FU), conventional chemotherapy used in clinics for cancer therapy. Inside intestinal mucosa, the 5-FU acts, leading to oxidative stress, stimulating the production/release of proinflammatory cytokines, local accumulation of neutrophils and consequent tissue damage. These alterations favor bacterial proliferation, triggering secondary infections, and are responsible for undesired effects such as myelosuppression and diarrhea. These factors negatively impact oncological patients' quality of life and explain why they commonly interrupt their treatment prematurely. Currently, there is no specific drug with the ability to completely avoid this condition, so the search for new molecules with pharmacological properties that can be used for preventing or ameliorating intestinal mucositis is important. Plumeria pudica is a plant that produces latexcontaining molecules with therapeutic potential. A protein fraction obtained from this latex (LPPp), which comprises a well-defined mixture of chitinases, proteinases proteinase inhibitors, was demonstrated to have antioxidant and anti-inflammatory activities, preserving tissue glutathione and malondialdehyde concentration, reducing superoxide dismutase and myeloperoxidase activity, and reducing the level of proinflammatory cytokines in different experimental models. Given this scenario, inflammation and oxidative stress are directly involved in the pathogenesis of intestinal mucositis promoted by 5-FU. So, the hypothesis is that LPPp could inhibit these factors to attenuate the cytotoxicity of this pathology associated with 5-FU-treatment. This article brings new insights into the potential of the laticifer proteins extracted from the latex of P. pudica and opens new perspectives for the treatment of this type of intestinal mucositis with LPPp.

Background: The gastrointestinal tract and the central nervous system are distinct because of evident morpho-functional features. Nonetheless, evidence indicates that these systems are bidirectionally connected through the gut-brain axis, defined as the signaling that takes place between the gastrointestinal tract and central nervous system, which plays in concert with the gut microbiota, i.e., the myriad of microorganisms residing in the lumen of the human intestine. In particular, it has been described that gut microbiota abnormalities, referred to as dysbiosis, may affect both central nervous system development and physiology. Objective: Starting from the possible mechanisms through which gut microbiota variations were found to impact several central nervous system disorders, including Autism Spectrum Disorder and Alzheimer’s Disease, we will focus on intriguing, although poorly investigated, aspects such as the epithelial and vascular barrier integrity. Indeed, several studies suggest a pivotal role of gut microbiota in maintaining the efficiency of both the intestinal barrier and blood-brain barrier. In particular, we report evidence indicating an impact of gut microbiota on intestinal barrier and blood-brain barrier homeostasis and discuss the differences and the similarities between the two barriers. Moreover, to stimulate further research, we review various tests and biochemical markers that can be used to assess intestinal and blood-brain barrier permeability. Conclusion: We suggest that the evaluation of intestinal and blood-brain barrier permeability in neurological patients may not only help to better understand central nervous system disorders but also pave the way for finding new molecular targets to treat patients with neurological impairment.

Background: Mushrooms are consumed worldwide due to their high nutritional and nutraceutical values. In addition to the presence of various vitamins, low-fat, and proteins, they are also an important source of trace elements, dietary fibers, and bioactive compounds. Their potential therapeutic properties are due to their multiple biological effects, such as antimicrobial, antiviral, antioxidant, anticancer, immune-modulating, cardioprotective, and antidiabetic properties. The global market of mushroom farming is anticipated to witness remarkable progress for its potential application in health products, profitable production and a rising demand for the healthy foods across the globe. The Asia Pacific marketplace seems to represent the major market of mushrooms, due to the higher per capita consumption of culinary and medical purposes. Mushrooms have generally low calories, low levels of cholesterol, fats, gluten and sodium. Several biological effects of mushroom are due to the presence of phenolic components, polysaccharides, terpenoids, terphenyl-related compounds, and many other lower molecular weight molecules. This review aims at describing the chemical characterization of several mushrooms species and their biological effects. Conclusion: The current review describes different secondary metabolites found in several mushrooms and mushrooms extracts, and the molecular mechanisms underlying the biological activities. Also the antimicrobial activities of mushrooms, mushrooms extracts and isolated compounds from mushrooms were described. The description of these activities, related to the presence of specific classes of secondary metabolites and isolated compounds, may lead to the identification of mycomplexes and mushrooms compounds that may be further studied for their potential application in nutraceutical products.

Background: LncRNA has been found to participate in a variety of biological processes and play an important role in the occurrence and development of tumors. Therefore, it is of vital clinical value to study the relationship between lncRNA and tumor. It has been confirmed that lncRNA affects tumor progression through sponge mRNA, regulation of signal pathways and activity of oncogenes. Recent studies have shown that LncRNA AGAP2-AS1 is closely related to tumor, because this review focuses on the molecular mechanism of LncRNA AGAP2-AS1 affecting tumor progression. Methods: The role of LncRNAAGAP2-AS1 in tumor was summarized by searching the literature related to LncRNAAGAP2-AS1 from PubMed in recent years. Results: LncRNA AGAP2-AS1 is abnormally expressed as an oncogene in tumors, which participates in biological processes such as tumor proliferation, migration, invasion and autophagy. LncRNA AGAP2-AS1 plays an important role in tumorigenesis and development by binding to mRNA, regulating signal pathway and affecting protein activity, which suggests that AGAP2- AS1 may play a great potential value in the treatment of human cancer. Conclusion: The abnormal expression of LncRNAAGAP2-AS1 plays an important role in the progression of tumor and has a promising value in the treatment of tumor. Exploring the molecular mechanism of lncRNA AGAP2-AS1 is of indispensable significance for tumor treatment.

Bacterial infections are a major cause of mortality and morbidity in humans throughout the world. Infections due to resistant bacterial strains such as methicillin-resistant Staphyloccocusaureus vancomycin, resistant Enterococci, Klebsiella pneumoniae, Staphylococcus aureus, and Mycobacterium are alarming. Hence the development of new antibacterial agents, which act via a novel mechanism of action, became a priority in antibacterial research. One such approach to overcome bacterial resistance is to target novel protein and develop antibacterial agents that act via different mechanisms of action. Bacterial GlmU is one such bifunctional enzyme that catalyzes the two consecutive reactions during the biosynthesis of uridine 5′-diphospho-Nacetylglucosamine, an essential precursor for the biosynthesis of bacterial cell wall peptidoglycan. This enzyme comprises two distinct active sites; acetyltransferase and uridyltransferase and both these active sites act independently during catalytic reactions. GlmU is considered an attractive target for the design and development of newer antibacterial agents due to its important role in bacterial cell wall synthesis and the absence of comparable enzymes in humans. Availability of three dimensions X-crystallographic structures of GlmU and their known catalytic mechanism from different bacterial strains have instigated research efforts for the development of novel antibacterial agents. Several GlmU inhibitors belonging to different chemical classes like 2- phenylbenzofuran derivative, quinazolines, aminoquinazolines, sulfonamides, arylsulfonamide, D-glucopyranoside 6-phosphates, terreic acid, iodoacetamide, N-ethyl maleimide, and Nethylmaleimide etc., have been reported in the literature. In the present review, we present an update on GlmU inhibitors and their associated antibacterial activities. This review may be useful for the design and development of novel GlmU inhibitors with potent antibacterial activity.

The human gut is a complex but stable micro-ecosystem in which the intestinal microbiota play a key role in human health, the health of the intestine and also affect the ability of the host to metabolize nutrients. Intestinal microbiota can affect human physiological functions by regulating host metabolism, immunity and intestinal barrier function. Dysbiosis in the intestinal microbiota is a crucial stimulus for the development of various diseases, which is associated with a variety of diseases in the body. The composition and function of intestinal microbiota depend on the host’s physiological status, genetic makeup, dietary habits, age, and environment, which are the risk factors for obesity, diabetes, cardiovascular diseases and tumors. Polyphenols are important plant secondary metabolites with many physiological functions like anti-oxidation, antitumor, bacteriostasis, cardiovascular and cerebrovascular prevention, and protection of liver and kidney and so on. A large number of studies have confirmed the benefits of dietary polyphenols to human health. Polyphenols and their associated metabolites affect intestinal health and the balance of intestinal microbiota by stimulating the growth of beneficial bacteria and inhibiting the proliferation of pathogens. This review aims to update the current knowledge and highlight how the bioactivities of polyphenols can modulate the intestinal microbiota and regulate the mechanisms of the microbiota, providing a theoretical basis and reference for the scientific and overall use of polyphenols to prevent and treat intestinal diseases and maintain human intestinal health.