Current Medicinal Chemistry - Volume 32, Issue 34, 2025

Cyclin-dependent kinases that are responsible for cell cycle control, have been studied for over 30 years as therapeutic targets for the treatment of cancer and inflammation. In the past twenty years, their activities in various viral infections have been investigated in the search of novel therapeutic strategies in the treatment of viral infections. The interest in evaluating antiviral activity of cyclin-dependent kinase inhibitors is closely linked to their role as host factors in viral replication. Due to the development of viral resistance, the strategies directed toward the targeting host machinery are still under investigation. This review is dedicated to the analysis of the molecular mechanisms of viral infection control by cyclin-dependent kinases that may reveal the potential mechanisms of action for their inhibitors and regulators as antiviral agents. We also consider recent efforts and achievements in the development of potential antiviral agents based on the cyclin-dependent kinase inhibitors and regulators, including their effects on various viruses, side effects, and toxicities.

CDK2 plays a pivotal role in controlling the cell cycle progression in eukaryotes and for this reason, it has been the subject of several studies for suitable inhibitors in the last decades. But more than 30 years of basic research have not generated an inhibitor as marketed drugs. Some inhibitors are to date in early phase clinical development. Moreover, most efforts to develop CDK2 inhibitors have been oriented towards orthosteric inhibitors, which block the kinase activity by binding to the ATP binding site, competing directly with ATP. These compounds have off-target kinase activity, because of the structural homology of the active sites of several other kinases. Targeting the CDK2 allosteric binding pocket could produce successful CDK2 inhibitors. Few examples of high-affinity allosteric CDK2 inhibitors are known. Despite promising research results, none has been approved for marketing. In recent years, various methodologies have been reported capable of identifying new and never-discovered portions of the target protein, which present adequate druggability characteristics. In this paper, we have highlighted and discussed the more recent findings on allosteric inhibitors intending to encouraging further exploration mainly focused on in silico drug discovery.

CDK2 plays a pivotal role in controlling the progression of the cell cycle and is a target for anticancer drugs. The last 30 years of structural studies focused on CDK2 provided the basis for understanding its inhibition and furnished the data to develop machine-learning models to study intermolecular interactions. This review addresses the application of computational models to estimate the inhibition of CDK2. It focuses on machine-learning models developed to predict binding affinity against CDK2 using the program SAnDReS. A search of previously published articles on PubMed showed machine-learning models built to evaluate CDK2 inhibition. BindingDB information for CDK2 furnished the data to generate updated machine-learning models to predict the inhibition of this enzyme. The application of SAnDReS to model CDK2-inhibitor interactions showed that this approach can build machine-learning models with superior predictive performance compared with classical and deep-learning scoring functions. Also, the innovative DOME analysis of the predictive performance of machine learning and universal scoring function indicates that this method is adequate to select computational models to address protein-ligand interactions. The available structural and functional data about CDK2 is a rich source of information to build machine-learning models to predict the inhibition of this protein target. SAnDReS can build superior models to predict pKi and outperform universal scoring functions, including one developed using deep learning.

Cyclin and cyclin-dependent kinases (CDKs) play a key role in the progression of the cell cycle including transcription, metabolism, apoptosis, etc. Different phases of the cell cycle like G1, S, G2, and M have specific cyclins and CDKs, each with specific functions as checkpoints to regulate the transfer of cells from one phase to another. The kinases ensure proper replication of DNA in the daughter cells while fault at any stage of the cell phase induces apoptosis of the faulty cell. Hence, CDKs are considered important targets for developing chemotherapeutics against cancers. So the published work on small molecules belonging to diverse chemical classes with potential CDK inhibitory and anticancer activities reported in the last ten years has been reviewed to give an overview of the chemical structures that may be employed in designing novel CDK inhibitors with improved cancer therapeutic. Literature search has been carried out using different search engines like Google, Elsevier, Science Direct, RSC, PubMed, etc. for the publications of small molecules as CDK inhibitors and anticancer agents. Several classes of molecules, including nitrogen heterocycles, macrocyclic, and natural products have been the most promising CDK inhibitors with anticancer activities. Though CDK 4/6 inhibition is most significant for anticancer activity and has been shown by most of the molecules but the inhibition to other CDKs including 1, 2, 7, 9 has also been observed. Further CDK4/6 inhibitors have been investigated for the treatment of breast cancer in combination with radiotherapy where no untoward toxicities were observed. Several molecules have shown promising CDKs inhibition with anticancer activities against different cancer cell lines. The most important class being of nitrogen heterocycles. Though some of these molecules are in different phases of clinical trials and there are many lead molecules for judicious structural modulation to develop more specific and selective CDKs inhibitors as anticancer agents.

The extracellular matrix (ECM) plays a pivotal role in maintaining tissue architecture and regulating cellular behavior. Recent insights have highlighted Discoidin Domain Receptors (DDRs) as critical mediators in cancer progression and therapeutic resistance. This editorial synthesizes the current understanding of DDR1 and DDR2, unique members of the receptor tyrosine kinase family activated by collagen, focusing on their distinct roles in cell-ECM interactions and cancer biology. We explore emerging therapeutic strategies targeting DDRs, with particular emphasis on differential approaches to DDR1 and DDR2 degradation. Additionally, we examine the complex relationship between DDR inhibition, degradation, and knockout phenotypes, presenting the novel DDR1 degrader LLC355 as a case study. By integrating findings from recent molecular investigations and clinical studies, we propose a comprehensive framework for DDR-targeted therapies in cancer treatment, highlighting their potential to overcome immune evasion mechanisms and enhance the efficacy of existing therapies.

Natural transformation refers to the process in which bacteria acquire new traits by uptaking naked DNA from the environment and integrating it into their genome through homologous recombination when they are in the specialized physiological state of competence. The natural transformation was first described in Streptococcus pneumoniae. Since Frederick Griffith first described natural transformations in S. pneumoniae in 1928, this phenomenon has been studied extensively. Induction of competence before natural transformation has been reported to involve about 10% of the pneumococcal genome. In addition to natural transformation, multiple physiological processes are involved, including biofilm formation, bacteriocin production, and fratricide. In this review, we summarized current knowledge about natural transformation in S. pneumoniae and described its competence regulation mechanism. This review also introduces the development of novel drugs and vaccines against S. pneumoniae infection by utilizing the existing knowledge of competence and natural transformation.

Addressing infectious conditions presents a formidable challenge, primarily due to the escalating issue of bacterial resistance. This, coupled with limited financial resources and stagnant antibiotic research, compounds the antibiotic crisis. Innovative strategies, including novel antibiotic development and alternative solutions, are crucial to combat microbial resistance. Nanotherapeutics offers a promising approach to enhance drug delivery systems. Integration into lipid-based nanoscale delivery systems, particularly through therapeutic substance encapsulation in liposomal carriers, significantly prolongs drug presence at infection sites. This not only reduces toxicity but also shields antibiotics from degradation. Lipidic carriers, particularly liposomes, exhibit remarkable specificity in targeting infectious cells. This holds great promise in combating antimicrobial resistance and potentially transforming treatment for multi-drug resistant infections. Leveraging liposomal carriers may lead to breakthroughs in addressing drug-resistant bacterial infections. This review emphasizes the potential of antimicrobial-loaded liposomes as a novel delivery system for bacterial infections. Encapsulating antimicrobial agents within liposomes enhances treatment efficiency. Moreover, liposomal systems counteract challenges posed by antimicrobial resistance, offering hope in managing persistent multidrug-resistant infections. In the battle against bacterial resistance and the antibiotics crisis, the use of antimicrobial-loaded liposomes as delivery vehicles shows great promise. This innovative approach not only extends drug effectiveness and reduces toxicity but also provides a path to address highly resistant infectious conditions. As research advances, liposomal nanotherapeutics may emerge as a transformative solution in the fight against bacterial infections.

Recently, increasing attention has been directed toward nutraceuticals, natural substances extracted from plants, fruits, or cereals. These compounds are well-known for their antibacterial, anti-inflammatory, antioxidant, and antitumor properties, with the latter being the primary focus of this review. The use of nutraceuticals, both as standalone treatments and in combination with standard chemotherapy, has been extensively studied through in vitro, in vivo experiments, and clinical trials for the prevention and treatment of various types of cancer, including breast, colon, pancreatic, prostate cancers, and leukemia. Findings from these studies emphasize the benefits of nutraceuticals in improving patient compliance and mitigating the adverse effects of conventional drugs. Specifically, the combination of nutraceuticals with chemotherapy allows for reduced dosages of synthetic drugs, thereby lessening their often-severe side effects. In this review, we explore the diverse mechanisms of action underlying the antitumor activity of key nutraceuticals-including curcumin, resveratrol, tocotrienols, ursolic acid, fisetin, gambogic acid, catechins, silibinin, berberine, emodin, piperine, deguelin, garcinol, plumbagin, zerumbone, and ginger. Furthermore, we summarize the most significant outcomes from clinical trials investigating these compounds. The clinical studies addressed various aspects of treatment, such as efficacy, safety, maximum tolerated doses, potential adverse effects, and patient compliance. The majority of the findings highlight the positive impact of combining nutraceuticals with chemotherapy, demonstrating enhanced therapeutic outcomes in anticancer treatments.

Sleep is necessary for long-term health and well-being. Sleep is divided into the rapid eye movement (REM), and non-rapid eye movement (NREM) stages. The normal sleep pattern follows a 90-minute cycle, and within those cycles, the body undergoes a regenerative state, restoring various components used daily. A sleep disorder can be due to multiple factors, i.e., genetic, environmental, and individual factors. Short and long-term effects of sleep deprivation can have harmful effects. The immune system requires sufficient sleep to maintain optimal function, and sleep deprivation leads to the release of proinflammatory cytokines, which dysregulate the function of the immune system. Sleep deprivation affects the central nervous system, resulting in cognitive impairments and diseases related to decreased prefrontal cortex activity. Sleep disturbance affects the hypothalamus, secreting corticotrophin-releasing hormone, which results in the release of adrenocorticotropic hormone. This leads to the secretion of cortisol and catecholamines. Sleep disturbance causes reduced muscle glycogen concentration and gives rise to various gastrointestinal problems. Sleep disturbance affects the cardiovascular system which results in hypertension, cardiac ischemia, congestive cardiac failure, and arrhythmia. Sleep disturbances affect the endocrine system leading to insulin resistance, obesity, and metabolic syndrome. Interestingly, treatment of obstructive sleep apnea with continuous positive airway pressure was found to enhance metabolic status. We discuss the pharmacological, non-pharmacological, and surgical treatment options for sleep disorders. Understanding the mechanism of sleep disturbance and its association with different systems of the body may help in better treatment outcomes.