Ischemic stroke (IS) is a globally prevalent cerebrovascular disorder resulting from cerebral vessel occlusion, leading to significant morbidity and mortality. The intricate pathological mechanisms underlying IS complicate the development of effective therapeutic interventions. Ferroptosis, a form of programmed cell death (PCD) characterized by iron overload and accumulation of lipid peroxidation products, has been increasingly recognized as a key contributor to IS pathology. Traditional Chinese medicines (TCMs) have long been utilized in the management of IS, prompting extensive research into their potential as sources of natural ferroptosis inhibitors. This review investigates the critical role of ferroptosis in IS and provides a comprehensive analysis of current research on natural ferroptosis inhibitors identified in TCMs, aiming to lay a theoretical groundwork for the development of innovative anti-IS therapies.

The development of natural inhibitors of polyphenol oxidase (PPO) is crucial in the prevention of enzymatic browning in fresh foods. However, few studies have focused on the effect of subsequent sterilization on their inhibition efficiency. This study investigated the influence and mechanism of high hydrostatic pressure (HHP) on the inhibition of PPO by epigallocatechin gallate (EGCG), cyanidin-3-O-glucoside (C3G), and ferulic acid. Results showed that under the conditions of 550 MPa/30 min, the activity of EGCG-PPO decreased to 55.92%, C3G-PPO decreased to 81.80%, whereas the activity of FA-PPO remained stable. Spectroscopic experiments displayed that HHP intensified the secondary structure transformation and fluorescence quenching of PPO. Molecular dynamics simulations revealed that at 550 MPa, the surface interaction between PPO with EGCG or C3G increased, potentially leading to a reduction in their activity. In contrast, FA-PPO demonstrated conformational stability. This study can provide a reference for the future industrial application of natural inhibitors.

Cancer poses a significant global health challenge and significantly contributes to mortality. NEK7, related to the NIMA protein kinase family, plays a crucial role in spindle assembly and cell division. The dysregulation of NEK7 is closely linked to the onset and progression of various cancers, especially colon and breast cancer, making it a promising target for cancer therapy. Nevertheless, the shortage of high-quality NEK7 inhibitors highlights the need for new therapeutic strategies. In this study, we utilized a multidisciplinary approach, including virtual screening, molecular docking, pharmacokinetics, molecular dynamics simulations (MDs), and MM/PBSA calculations, to evaluate natural compounds as NEK7 inhibitors comprehensively. Through various docking strategies, we identified three natural compounds: (-)-balanol, digallic acid, and scutellarin. Molecular docking revealed significant interactions at residues such as GLU112 and ALA114, with docking scores of -15.054, -13.059, and -11.547 kcal/mol, respectively, highlighting their potential as NEK7 inhibitors. MDs confirmed the stability of these compounds at the NEK7-binding site. Hydrogen bond analysis during simulations revealed consistent interactions, supporting their strong binding capacity. MM/PBSA analysis identified other crucial amino acids contributing to binding affinity, including ILE20, VAL28, ILE75, LEU93, ALA94, LYS143, PHE148, LEU160, and THR161, crucial for stabilizing the complex. This research demonstrated that these compounds exceeded dabrafenib in binding energy, according to MM/PBSA calculations, underscoring their effectiveness as NEK7 inhibitors. ADME/T predictions showed lower oral toxicity for these compounds, suggesting their potential for further development. This study highlights the promise of these natural compounds as bases for creating more potent derivatives with significant biological activities, paving the way for future experimental validation.

The localization of lipoprotein (Lol) system is responsible for the transport of lipoproteins in the outer membrane (OM) of Vibrio parahaemolyticus. LolB catalyzes the last step in the Lol system, where lipoproteins are inserted into the OM. If the function of LolB is impeded, growth of V. parahaemolyticus is inhibited, due to lack of an intact OM barrier for protection against the external environment. Additionally, it becomes progressively harder to generate antimicrobial resistance (AMR). In this study, LolB was employed as the receptor for a high-throughput virtual screening from a natural compounds database. Compounds with higher glide score were selected for an inhibition assay against V. parahaemolyticus. It was found that procyanidin, stevioside, troxerutin and rutin had both exciting binding affinity with LolB in the micromolar range and preferable antibacterial activity in a concentration-dependent manner. The inhibition rates of 100 ppm were 87.89%, 86.2%, 91.39% and 83.71%, respectively. The bacteriostatic mechanisms of the four active compounds were explored further via fluorescence spectroscopy and molecular docking, illustrating that each molecule formed a stable complex with LolB via hydrogen bonds and pi-pi stacking interactions. Additionally, the critical sites for interaction with V. parahaemolyticus LolB, Tyr108 and Gln68, were also illustrated. This paper demonstrates the inhibition of LolB, thus, leading to antibacterial activity, and identifies LolB as a promising drug target for the first time. These compounds could be the basis for potential antibacterial agents against V. parahaemolyticus.

Non-alcoholic fatty liver disease (NAFLD), a spectrum of liver disorders from non-alcoholic fatty liver (NAFL) to the more severe non-alcoholic steatohepatitis (NASH), is the leading etiology of chronic liver disease and its global prevalence is increasing. Hepatic steatosis, a condition marked by an abnormal buildup of triglycerides in the liver, is the precursor to NAFLD. Differentiated cluster 36 (CD36), a scavenger receptor class B protein, is a membrane receptor that recognizes multiple lipid and non-lipid ligands. It is generally agreed that CD36 contributes significantly to hepatic steatosis by taking part in fatty acid uptake as well as triglyceride storage and secretion. While there has not been any conclusive research on how CD36 inhibitors prevent NAFLD from progressing and no clinically approved CD36 inhibitors are currently available for use in NAFLD, CD36 remains a target worthy of further investigation in NAFLD. In recent years, the potential role of natural products acting through CD36 in treating non-alcoholic fatty liver disease has attracted much attention. This paper offers an overview of the pathogenesis of CD36 in NAFLD and summarizes some of the natural compounds or extracts that are currently being investigated for modulating NAFLD via CD36 or the CD36 pathway, providing an alternative approach to the development of CD36-related drugs in NAFLD.

Coronaviruses have been receiving continuous attention worldwide as they have caused a serious threat to global public health. This group of viruses is named so as they exhibit characteristic crown-like spikes on their protein coat. SARS-CoV-2, a type of coronavirus that emerged in 2019, causes severe infection in the lower respiratory tract of humans and is often fatal in immunocompromised individuals. No medications have been approved so far for the direct treatment of SARS-CoV-2 infection, and the currently available treatment options rely on relieving the symptoms. The medicinal plants occurring in nature serve as a rich source of active ingredients that could be utilized for developing pharmacopeial and non-pharmacopeial/synthetic drugs with antiviral properties. Compounds obtained from certain plants have been used for directly and selectively inhibiting different coronaviruses, including SARS-CoV, MERS-CoV, and SARS-CoV-2. The present review discusses the potential natural inhibitors against the highly pathogenic human coronaviruses, with a systematic elaboration on the possible mechanisms of action of these natural compounds while acting in the different stages of the life cycle of coronaviruses. Moreover, through a comprehensive exploration of the existing literature in this regard, the importance of such compounds in the research and development of effective and safe antiviral agents is discussed. We focused on the mechanism of action of several natural compounds along with their target of action. In addition, the immunomodulatory effects of these active components in the context of human health are elucidated. Finally, it is suggested that the use of traditional medicinal plants is a novel and feasible remedial strategy against human coronaviruses.

Introduction: Protein tyrosine phosphatase 1B (PTP1B) inhibition has been recommended as a crucial strategy to enhance insulin sensitivity in various cells and this fact is supported by human genetic data. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. In the latter years, targeting PTP1B inhibitors is being considered an attractive target to treat T2DM and therefore libraries of PTP1B inhibitors are being suggested as potent antidiabetic drugs. Areas covered: This review provides an overview of published patents from January 2015 to December 2018. The review describes the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat type 2 diabetes. Expert opinion: Enormous developments have been made in PTP1B drug discovery which describes progress in natural products, synthetic heterocyclic scaffolds or heterocyclic hybrid compounds. Various protocols are being followed to boost the pharmacological effects of PTP1B inhibitors. Moreover these new advancements suggest that it is possible to get small-molecule PTP1B inhibitors with the required potency and selectivity. Furthermore, future endevours via an integrated strategy of using medicinal chemistry and structural biology will hopefully result in potent and selective PTP1B inhibitors as well as safer and more effective orally available drugs.

Quantum mechanical approaches for the massive computation on large biological system such as virtual screening in drug design and development have presented a challenge to computational chemists for many years. In this study, we demonstrated that by taking advantage of rapid growth of GPU-based hardware and software (i.e., teraChem), it is feasible to perform virtual screening of a refined chemical library at quantum mechanical level in order to identify the lead compounds with improved accuracy, especially for the drug targets such as metalloproteins in which significant charge transfer and polarization occur amongst the metal ions and their coordinated amino acids. Our calculations predicted four nature compounds (i.e., Curcumin, Catechin, menthol, and Ferulic acid) as the suitable inhibitors for antibiotics resistance against New Delhi Metallo-β-lactamase-1 (NDM-1). Molecular orbitals (MOs) of the QM region of metal ions and their coordinated residues indicate that the bridged hydroxide ion delocalized the electron over the Zn-OH-Zn group at HOMO, different from MOs when the OH- is not presented in NDM-1. This indicates that the bridged hydroxide ion plays an important role in the design of antibiotics and other inhibitors targeting the metalloproteins.

Cancer cells are more addictive to MTH1 than normal cells because of their dysfunctional redox regulations. MTH1 plays an important role to maintain tumor cell survival, while it is not indispensable for the growth of normal cells. Farnesyl phenols having a coumaroyl substitution are rather uncommon in nature. Eight farnesyl phenolic compounds with such substituent moiety (1-8), including six new ones, ganosinensols E-J (1-6) were isolated from the 95% EtOH extract of the fruiting bodies of Ganoderma sinense. Four pairs of enantiomers 1/2, 3/4, 5/6 and 7/8 were resolved by HPLC using a Daicel Chiralpak IE column. Their structures were elucidated from extensive spectroscopic analyses and comparison with literature data. The absolute configurations of C-1\' in 1-6 were assigned by ECD spectra. These compounds were predicted to have high binding affinity to MTH1 through virtual ligand screening. The enzyme inhibition experiments and cell-based assays confirmed their inhibitory effects on MTH1. Furthermore, siRNA knockdown experiments and the cellular thermal shift assay (CETSA) confirmed that the farnesyl phenolic enantiomers specifically bound with MTH1 in intact cells. Meanwhile, the low cytotoxicity of 1-8 on normal human cells further verified their good selectivity and specificity to MTH1. These active structures are expected to be potential anti-cancer lead compounds.

Mammalian carboxylesterases (CEs) are important serine hydrolases catalyzing the hydrolysis of ester- or amide-containing compounds into the corresponding alcohols and carboxylic acids. In human, two primary carboxylesterases including hCE1 and hCE2 have been identified and extensively studied in the past decade. hCE1 is known to play crucial roles in the metabolism of a wide variety of endogenous esters, clinical drugs and insecticides, while hCE2 plays a key role in the metabolic activation of anticancer agents including irinotecan and capecitabine. The key roles of hCEs in both human health and xenobiotic metabolism arouse great interest in the discovery of potent and selective hCEs inhibitors to modulate endobiotic metabolism or to improve the outcomes of patients administrated with ester drugs. This review covers the significance and recent progress in the discovery of natural inhibitors against hCEs. The tools for screening and characterization of inhibitors against human CEs, including traditional LC-based approaches and the newly developed optical substrate-based assays, are summarized and discussed for the first time. Furthermore, the structural information and inhibitory capacities of all reported hCEs inhibitors including fatty acids, flavonoids, tanshinones and triterpenoids have been systematically summarized. All information and knowledge presented in this review will be very helpful for medicinal chemists to develop more potent and highly selective inhibitors against hCEs for potential biomedical applications.