Immunotherapy, particularly targeting the PD-1/PD-L1 pathway, holds promise in cancer treatment by regulating the immune response and preventing cancer cells from evading immune destruction. Nonetheless, this approach poses a risk of unwanted immune system activation against healthy cells. To minimize this risk, our study proposes a strategy based on selective targeting of the PD-L1 pathway within the acidic microenvironment of tumors. We employed in silico methods, such as virtual screening, molecular mechanics, and molecular dynamics simulations, analyzing approximately 10,000 natural compounds from the MolPort database to find potential hits with the desired properties. The simulations were conducted under two pH conditions (pH = 7.4 and 5.5) to mimic the environments of healthy and cancerous cells. The compound MolPort-001-742-690 emerged as a promising pH-selective inhibitor, showing a significant affinity for PD-L1 in acidic conditions and lower toxicity compared to known inhibitors like BMS-202 and LP23. A detailed 1000 ns molecular dynamics simulation confirmed the stability of the inhibitor-PD-L1 complex under acidic conditions. This research highlights the potential of using in silico techniques to discover novel pH-selective inhibitors, which, after experimental validation, may enhance the precision and reduce the toxicity of immunotherapies, offering a transformative approach to cancer treatment.

Alzheimer\'s disease (AD) is a neurological disease, and its signs and symptoms appear slowly over time. Although current Alzheimer\'s disease treatments can alleviate symptoms, they cannot prevent the disease from progressing. To accurately diagnose and treat Alzheimer\'s disease, it is therefore necessary to establish effective methods for diagnosis. Apolipoprotein E4 (ApoE4), the most frequent genetic risk factor for AD, is expressed in more than half of patients with AD, making it an attractive target for AD therapy. We used molecular docking simulations, classical molecular mechanics optimizations, and ab initio fragment molecular orbital (FMO) calculations to investigate the specific interactions between ApoE4 and the naturally occurring compounds found in the plant Moringa Oleifera. According to the FMO calculations, quercetin had the highest binding affinity to ApoE4 among the sixteen compounds because its hydroxyl groups generated strong hydrogen bonds with the ApoE4 residues Trp11, Asp12, Arg15, and Asp130. As a result, we proposed various quercetin derivatives by introducing a hydroxyl group into quercetin and studied their ApoE4 binding properties. The FMO data clearly showed that adding a hydroxyl group to quercetin improved its binding capacity to ApoE4. Furthermore, ApoE4 Trp11, Asp12, Arg15, and Asp130 residues were discovered to be required for significant interactions between ApoE4 and quercetin derivatives. They had a higher ApoE4 binding affinity than our previously proposed epicatechin derivatives. Accordingly, the current results evaluated using the ab initio FMO method will be useful for designing potent ApoE4 inhibitors that can be used as a candidate agent for AD treatment.

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.

For centuries, natural products (NPs) have served as powerful therapeutics against a variety of human ailments. Nowadays, they still represent invaluable resources for the treatment of many diseases, including bacterial infections. After nearly three decades since the World Health Organization\'s (WHO) declaration of tuberculosis (TB) as a global health emergency, Mycobacterium tuberculosis (Mtb) continues to claim millions of lives, remaining among the leading causes of death worldwide. In the last years, several efforts have been devoted to shortening and improving treatment outcomes, and to overcoming the increasing resistance phenomenon. Nature has always provided a virtually unlimited source of bioactive molecules, which have inspired the development of new drugs. NPs are characterized by an exceptional chemical and structural diversity, the result of millennia of evolutionary responses to various stimuli. Thanks to their favorable structural features and their enzymatic origin, they are naturally prone to bind proteins and exhibit bioactivities. Furthermore, their worldwide distribution and ease of accessibility has contributed to promote investigations on their activity. Overall, these characteristics make NPs excellent models for the design of novel therapeutics. This review offers a critical and comprehensive overview of the most promising NPs, isolated from plants, fungi, marine species, and bacteria, endowed with inhibitory properties against traditional and emerging mycobacterial enzymatic targets. A selection of 86 compounds is here discussed, with a special emphasis on their biological activity, structure-activity relationships, and mechanism of action. Our study corroborates the antimycobacterial potential of NPs, substantiating their relevance in future drug discovery and development efforts.

Biofilms represent an adaptive lifestyle where microbes grow as structured aggregates in many different environments, e.g. on body surfaces and medical devices. They are a profound threat in medical (and industrial) settings and cause two-thirds of all infections. Biofilm bacteria are especially recalcitrant to common antibiotic treatments, demonstrating adaptive multidrug resistance. For this reason, novel methods to eradicate or prevent biofilm infections are greatly needed. Recent advances have been made in exploring alternative strategies that affect biofilm lifestyle, inhibit biofilm formation, degrade biofilm components and/or cause dispersal. As such, naturally derived compounds, molecules that interfere with bacterial signaling systems, anti-biofilm peptides and phages show great promise. Their implementation as either stand-alone drugs or complementary therapies has the potential to eradicate resilient biofilm infections. Additionally, altering the surface properties of indwelling medical devices through bioengineering approaches has been examined as a method for preventing biofilm formation. There is also a need for improving current biofilm detection methods since in vitro methods often do not accurately measure live bacteria in biofilms or mimic in vivo conditions. We propose that the design and development of novel compounds will be enabled by the improvement and use of appropriate in vitro and in vivo models.

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Cyclin-Dependent Kinases (CDKs) are well-known reliable targets for cancer treatment being often deregulated. Among them, since the transcription-associated CDK9 represents the sentry of cell transcriptional homeostasis, it can be a valuable target for managing cancers in which the transcriptional machinery is dysregulated by tumor-driver oncogenes. Here we give an overview of some natural compounds identified as CDK inhibitors with reported activity also against CDK9, that were taken as a model for the development of highly active synthetic anti-CDK9 agents. After, we summarize the data on CDK9 inhibition in a group of rare pediatric solid tumors such as rhabdomyosarcoma, Ewing\'s sarcoma, synovial sarcoma and malignant rhabdoid tumors (soft tissue sarcomas), highlighting the more recent results in this field. Finally, we discuss the perspective and challenge of CDK9 modulation in cancer.

Human papillomaviruses (HPV) are a group of strong human carcinogen viruses considered to be the fourth leading cause of mortality among women in the world. HPV is the most important cause of cervical cancer, which is the second most common cancer in women living in low and middle-income countries. To date, there is no effective cure for an ongoing HPV infection; therefore, it is required to investigate anticancer drugs against this life-threatening infection. In this study, we collected more than 100 plant-derived compounds with anti-cancer and antiviral potentials from a variety of papers. Smile formats of these compounds (ligand), were harvested from PubChem database and examined based on the absorption, distribution, metabolism, excretion, and toxicity properties by programs such as Swiss ADME, admetSAR, and pkCSM. Twenty compounds, which were likely to be the HPV16E6 inhibitor, were selected for docking calculations. We examined these natural inhibitors against the HPV16 E6 oncogenic protein. Eventually, three of these compounds were used as the most potent inhibitors (Ginkgetin (peculiarly), Hypericin and Apigetrin) were probably used as the possible source of cancer treatment caused by E6 oncoprotein. In this research, we conducted the docking calculations by Autodock 4.2.6 software. Docking analysis showed the interaction of these plant-originated inhibitors with E6AP, p53, and Myc binding sites on the E6 oncoprotein which support the normal function of E6AP, p53, and Myc.

Lung cancer ranks number one among the all cancer types in the world, out of which 85% are non-small cell lung cancer (NSCLC). In case of NSCLC, a substitution mutation of Leu 858 Arg (L858R) in the gene of Epidermal Growth Factor Receptor (EGFR) has been reported. Hence, targeting EGFR containing L858R mutation using inhibitors is well reported strategy to discover potential drugs against NSCLC. The present work aims to identify the potent inhibitors against EGFR L858R from Vernonia cinerea plant. A library of 45 phytochemicals was subjected to virtual screening using rigid and flexible docking. 12 potential phytochemicals were screened by molecular docking with high binding energy (between -8.0 and -9.7 kcal mol-1). Two compounds viz., luteolin -7-glucoside and epicatechin gallate showed interaction with Met793 of EGFR-L858R which was similar to the reference inhibitor PD168393. To analyze the stability of the luteolin -7-glucoside and epicatechin gallate with EGFR L858R, molecular dynamics simulations were conducted in explicit water conditions using 60 nanosecond. The results of hydrogen bonding patterns, radius of gyration, deviations in conformational elements, fluctuations in the residual components, and solvent accessible surface area revealed better stability of luteolin -7-glucoside and epicatechin gallate with EGFR-L858R as compared to PD168393. Therefore, we conclude that luteolin -7-glucoside and epicatechin gallate have excellent inhibition properties thus they can be used further to develop effective drugs against lung cancer having EGFR-L858R mutation.Communicated by Ramaswamy H. Sarma.

Introduction: Chikungunya virus (CHIKV), a reemerging human arthropod borne virus, can causes global epidemic outbreaks and has become a serious health concern due to the unavailability of any antiviral therapy/vaccine. Extensive research has been conducted to target different proteins from CHIKV to curtail the spread of virus.Areas covered: This review provides an overview of the granted patents including the current status of antiviral strategies targeting CHIKV.Expert opinion: Under the current scenario, potential molecules and different approaches have been utilized to suppress CHIKV infection. MV-CHIKV and VRC-CHKVLP059-00-VP vaccine candidates have successfully completed phase I clinical trials and ribavirin (inhibitor) has shown significant inhibition of CHIKV replication and could be the most promising candidates. The drug resistance and toxicity can be modulated by using the inhibitors/drugs in combination. Moreover, nanoparticle formulations can improve the efficacy and bioavailability of drugs.