Mini Reviews in Medicinal Chemistry - Online First

The drug discovery process is highly intricate and complex. Driven by unprecedented advances in AI technology, the application of artificial intelligence in drug discovery (AIDD) is showing significant growth, and AIDD has the potential to fundamentally change and revolutionize traditional drug development models in the foreseeable future. We selected 7061 literature studies on artificial intelligence used in drug discovery from the Web of Science Core Collection database from 2000 to 2024, and adopted bibliometric tools, such as Citespace, VOSviewer, and RStudio, to select nodes for knowledge graph generation and visualization analysis by using country, institution, author, and keywords. The results showed that from 2017 to 2024, the literature on the use of artificial intelligence for drug discovery exploded, with the United States having the largest number of papers, and China's number of papers growing rapidly and surpassing the United States in the last two years. Molecular docking, virtual screening, algorithm optimization, interpretable AIDD, protein language modeling, drug targets, and protein interaction prediction were found to be the research hotspots in this field in recent years. AI has been widely used in the field of drug research and development. Based on the quantitative analysis of the literature on the use of artificial intelligence in drug discovery, this paper has revealed the current research status in this field, clarified the current research hotspots and future research trends, and provided certain references for researchers to plan future research directions.

The method of discovering new drugs is costly, time-consuming, laborious, and associated with a high failure rate. Various techniques have been applied in modern drug discovery to resolve these issues and discover novel pharmacologically active agents. Natural products are one of the sources of drugs that have long been used to treat various illnesses. Kojic acid (KA) is a naturally produced bioactive chemical with a 3-hydroxy-4-pyranone skeleton made by numerous aerobic microbes, such as Aspergillus and Penicillium. KA is a potent tyrosinase inhibitor used in cosmetics to lighten skin by reducing hyperpigmentation. In this review, beyond its cosmetic applications, it exhibits versatile biological activities, including anticancer, antibacterial, antifungal, antioxidant, antiviral, anti-inflammatory, anticonvulsant, anti-Alzheimer's disease, antidiabetic, and metal-chelating properties. KA and its analogs have been reported as promising radioprotective agents capable of mitigating the harmful effects of ionizing radiation. By integrating KA with pharmacologically active scaffolds, researchers have developed potent hybrids, such as amino-chloroquinoline-KA derivatives, which demonstrate vigorous β-hematin inhibitory activity and significant efficacy against both delicate and resilient strains of P. falciparum to chloroquine. The approach taken to prepare this review article involved collecting, assessing, and synthesizing relevant literature from different databases. This review systematically explores the comprehensive therapeutic potential of KA and its derivatives, including Mannich base, thiazoles, and 1,2,3-triazoles, for various activities, with Michael Adducts and dinuclear ruthenium complexes which exhibits promising antitumor activity. Combining current knowledge will provide a comprehensive foundation for the rational design and development of clinically relevant agents based on KA pharmacophores.

In the ongoing battle between the immune system and cancer, a unique subset of T cells has quietly emerged as a key player. Tissue-Resident Memory T (TRM) cells, strategically positioned within tissues, are redefining our understanding of localized immune defense and tumor control. This review aims to bridge this knowledge gap by synthesizing current concepts of T cell immune surveillance with foundational aspects of TRM cell biology. We explored clinical evidence supporting the prognostic and therapeutic relevance of TRM cells in various cancer contexts, including their emerging roles in enhancing responses to immunotherapy. Furthermore, we discussed innovative strategies that exploit TRM-phenotype cells for patient stratification, disease staging, and therapeutic development. Key challenges such as the absence of standardized T cell nomenclature and the limited understanding of how TRM markers relate to tumor biology are critically examined. By integrating basic science and clinical observations, this review provides a comprehensive overview of the field and highlights promising avenues for future research to harness TRM cells in precision oncology.

Since its discovery in 1979, the tumor suppressor p53 has been widely studied and expressed in various organisms, including yeast. Yeast has proven to be a very informative model and an effective system for studying the roles and functions of this protein and gene. This review is a compilation of our team's studies involving p53 expression in yeast. These researches investigated certain aspects, essentially the apoptotic function of p53. Our main contribution to the study and understanding of the p53 gene in the yeast context is the confirmation of a negative effect of p53 on cell growth in both Saccharomyces cerevisiae and Pichia pastoris strains, which ultimately led to apoptotic cell death. This involves a high dose of p53 and the NLS signal, which enables p53 to target both the mitochondria and the nucleus. Prior to that, obtaining the whole protein required a cDNA without its UTR. Thus, a yeast model was developed, allowing verification of p53 activity. Cancer mutants and their revertants could thereby be assessed. This has evolved into a real antioxidant/anti-apoptotic molecular screening mechanism. Two primary applications were achieved: testing the co-expression with the thioredoxin 2 gene (TRX2) and assessing the impact of Nigella sativa seed extracts. Furthermore, the high yield of yeast P53 production allowed its use in serological cancer diagnosis.

Fragment-based drug discovery (FBDD) has emerged as a transformative strategy in modern medicinal chemistry, offering a rational and efficient alternative to traditional high-throughput screening (HTS). By utilizing small, low-molecular-weight fragments with moderate binding affinity, FBDD enables systematic optimization into potent lead compounds with improved physicochemical properties. Its modular and ligand-centric nature has proven particularly advantageous in accelerating early-stage drug discovery. The COVID-19 pandemic highlighted the adaptability of FBDD, as fragment screening and computational modeling rapidly identified inhibitors of the SARS-CoV-2 main protease (M^pro). Integration with artificial intelligence (AI) and cloud-based platforms further enhanced the speed and global accessibility of fragment campaigns, setting a precedent for collaborative, open-science initiatives. Beyond infectious diseases, FBDD has demonstrated significant promise in oncology, antibacterial therapy, and neurodegenerative disorders, reflecting its versatility across diverse therapeutic landscapes. Recent technological advances have expanded the scope of FBDD. High-resolution cryo-electron microscopy and AI-driven structural prediction now enable the exploration of previously inaccessible or dynamic protein targets. Emerging modalities, such as PROTACs and RNA-targeted therapeutics, also intersect with fragment-based strategies, opening avenues for addressing so-called “undruggable” proteins. Despite persistent challenges, including the need for sensitive biophysical methods and sophisticated infrastructure, the approach continues to evolve. Looking ahead, the convergence of FBDD with machine learning, open-access fragment libraries, and global research collaboration positions it as a scalable, adaptive platform for drug discovery. As future health threats demand rapid innovation, FBDD is poised to remain a cornerstone of both academic and industrial research pipelines.

MicroRNAs (miRNAs) are integral to the regulation of gene expression pertinent to cardiovascular health, affecting various biological processes, such as cell adhesion, inflammation, and lipid metabolism. Certain miRNAs (miR-1, miR-133a, miR-133b, miR-208a, etc.) have been associated with a range of cardiovascular disorders, including atherosclerosis, arrhythmias, and myocardial infarction, indicating their potential utility as therapeutic targets and biomarkers. Nevertheless, the therapeutic application of miRNAs is constrained by their inherent instability and suboptimal cellular uptake, which can be attributed to their negative charge and vulnerability to degradation. To mitigate these challenges, a variety of delivery systems have been developed, encompassing both viral vectors (such as adeno-associated viruses, adenoviruses, and lentiviral vectors) and non-viral vectors (including liposomes and polymer nanoparticles). Besides, the integration of nanoparticles, extracellular vesicles, and a hydrogel system can enhance the stability, targeting, and efficiency of miRNA delivery. Furthermore, advanced systems, such as intelligent responsive delivery mechanisms and multifunctional joint delivery systems, are currently under investigation to improve therapeutic outcomes. Notably, studies exploring poly (β-amino esters) as a non-viral gene delivery vector have demonstrated potential in advancing gene therapy for cardiovascular diseases. This article reviews the role of miRNAs in cardiovascular disease pathogenesis and therapy, discusses recent progress in miRNA delivery strategies, and summarizes clinical challenges and highlights the critical need for continuous innovation in delivery systems to enhance treatment efficacy, ensure safety, and facilitate industrial scalability.

Neem gum, a biocompatible and biodegradable polysaccharide, has broad applications in drug delivery and tissue engineering. Its hydrophilic and bioadhesive properties make it ideal for controlled drug release and scaffold fabrication. This review examines the role of neem and its derivatives in pharmaceutical formulations, wound healing, and regenerative medicine, while addressing stability, scalability, and regulatory considerations. Future directions include the integration of nanotechnology and chemical modifications for enhanced biomedical applications. Neem gum has been developed into various forms, including hydrogels, nanoparticles, films, and coatings, for targeted drug delivery and tissue regeneration. Its antimicrobial, antioxidant, and anti-inflammatory properties enhance wound healing and infection control, but challenges like batch variability and mechanical limitations remain. Neem gum is a promising natural biomaterial for pharmaceutical and biomedical applications. Further research on stability, large-scale processing, and clinical validation is essential for commercialisation and clinical use.

Stress granules (SGs) are membraneless cytoplasmic condensates formed through liquid-liquid phase separation (LLPS) in response to diverse cellular stressors. These dynamic macromolecular complexes serve as critical signaling hubs that orchestrate adaptive responses by sequestering translationally stalled mRNAs, RNA-binding proteins, and key signaling molecules. Substantial evidence implicates SGs in the pathogenesis of numerous disorders, where they dysregulate essential cellular pathways, including stress-induced cell death cascades. While regulated cell death constitutes a physiological process vital for tissue homeostasis, aberrant or excessive cell death represents a pathogenic driver in neurodegeneration, ischemic injuries, autoimmune disorders, infectious diseases, and oncological pathologies. Consequently, deciphering the molecular governance of cell death holds great potential for developing novel therapeutics. Although proteomic analyses reveal that SGs sequester multiple cell death regulators, the precise mechanisms through which these components modulate death pathways remain incompletely resolved. This review systematically examines the causal relationships between SGs dynamics and major cell death modalities, including apoptosis, necroptosis, pyroptosis, and ferroptosis. By synthesizing recent advances in SG biology and cell death regulation, we elucidate how stress-adapted SG proteomes functionally contribute to death pathway activation or suppression. This mechanistic synthesis not only resolves current controversies regarding SGs’ function in different cell death models but also identifies targetable vulnerabilities at the SGs-death pathway interface, offering innovative frameworks for treating SGs-associated pathologies.