Current Topics in Medicinal Chemistry - Online First

A biosensor is a biological device designed to convert biological responses into an electrical signal, which has diverse applications across various fields, including diagnostics, environmental monitoring, food safety, and drug discovery. Among these, biosensing technology has achieved remarkable success in medical diagnostics. To detect target molecules for various probe molecules, such as nucleic acids, peptides, antibodies, and proteins are widely used. Of these, antibodies are well-established as remarkable molecules for detecting and monitoring a broad range of analytes. Recently, a novel class of molecules known as aptamers, often referred to as “artificial antibodies,” has gained significant attention from researchers for numerous biomedical applications, particularly in biosensing. Aptamers are synthetic molecules generated through a method called Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Since aptamer and antibody have different bindings for target molecules, various biosensing techniques are utilized by using the combination of aptamer and antibody to enhance the biosensor. This combination possesses a unique and beneficial feature and holds the potential to drive significant advancements in sensing technology. Applying these combinations in biosensing technologies has some limitations due to the aptamer generation for some particular targets. This review explores recent applications of antibodies, aptamers, and their combined use in enhancing biosensing technologies and their limitations.

The field of cancer research has witnessed a surge in the exploration of novel therapeutic agents, with pyrazole derivatives emerging as promising candidates in the quest for effective anticancer treatments. This comprehensive review provides an in-depth analysis of the research landscape surrounding pyrazole derivatives as potential anticancer agents over the period from 2012 to 2024. Many synthetic pyrazole derivatives have been approved by the FDA and used as chemotherapeutic medicines, and some are under clinical trials, also reported in this article. The review aims to serve as a valuable resource for researchers, guiding future investigations and fostering the development of innovative pyrazole-based anticancer therapeutics.

Neurodegenerative diseases present a considerable challenge to healthcare systems worldwide, prompting the exploration of innovative treatment strategies. Heterocyclic compounds, specifically those originating from the indole and imidazole structures, have garnered increasing interest due to their potential to protect neurons. Based on an in-depth literature survey, this review explores the Structure-Activity Relationship (SAR) and pharmacokinetics to reveal the active pharmacophores of various indole and imidazole analogs. We delve into the underlying molecular and cellular mechanisms involved in neurodegeneration, highlighting how indole and imidazole derivatives exert neuroprotective effects by modulating oxidative stress, inflammation, protein misfolding, inhibiting cholinesterase, and neuroinflammation. Finally, we address the challenges and prospects in translating these findings into clinical therapies, underscoring the need for continued research to optimize the safety and efficacy of heterocyclic compounds in the treatment of neurodegenerative disorders.

Experimental-driven directed evolution has achieved remarkable success in enzyme engineering. However, it relies on random mutagenesis and high-throughput screening, both of which have certain limitations, particularly the randomness of mutagenesis and the extensive screening workload that slows down the method's rapid development. In contrast, computer-aided directed evolution combines computational simulations with experimental techniques, providing an efficient and precise approach to enzyme rational design and optimization. By integrating computational tools, researchers can streamline the enzyme design process, improving the accuracy of mutations and screenings, which in turn accelerates enzyme optimization. This review comprehensively introduces the commonly used methods and applications of computer-aided directed evolution, discussing the tools and techniques frequently used in protein sequence analysis and structural analysis. It also covers computational simulation and prediction strategies such as homology modeling, molecular docking, molecular dynamics simulations, machine learning algorithms, and virtual screening. These tools play a critical role in predicting the effects of mutations on enzyme function and optimizing enzyme performance. Moreover, the review explores widely adopted semi-rational and rational design strategies in enzyme engineering, which combine computational predictions with experimental validation to effectively improve enzyme performance. Additionally, the article delves into the challenges and bottlenecks encountered in applying computational technologies in directed evolution, including issues related to computational precision, data quality, and the complexity of enzyme-substrate interactions. Despite these challenges, the future of computer-aided directed evolution holds great promise, with advancements in computational power, machine learning, and multi-omics data integration offering tremendous potential to overcome current limitations.

In conclusion, this review aims to provide valuable insights for researchers in enzyme engineering, assisting them in developing new, efficient enzymes by integrating both experimental and computational approaches.

Researchers are actively engaged in developing new antitubercular drugs targeting the enzyme Mycobacterial Thymidine Monophosphate Kinase (MtbTMPK). This newer target has specificity and selectivity over other thymidylate kinases and especially differs from human thymidylate kinase (hTMPK). Over the last two decades, various potent MtbTMPK inhibitors comprised of both nucleoside and non-nucleoside structures have been developed. Mostly, nucleoside inhibitors have encountered substantial challenges, primarily related to poor solubility and permeability, which often render them inactive in whole-cell antitubercular assays. Consequently, the focus has shifted towards identifying potent non-nucleoside inhibitors that demonstrate activity in whole-cell assays. Researchers have employed structure-based modifications and leveraged insights from co-crystal structures of Mycobacterium tuberculosis TMPK (MtbTMPK) with its natural substrate, thymidine monophosphate (TMP), to develop potent non-nucleoside inhibitors—such as cynopyridone and 5-methylpyridine analogues—which have demonstrated nanomolar enzyme inhibitory activity. However, the problem was persistent and only a few non-nucleoside inhibitors have been found to be active in whole-cell activity, likewise nucleoside inhibitors. The reason behind the uncertainty between enzyme inhibitory and whole cell antitubercular activity of developed inhibitors remains incomprehensible to date, even though the efflux pump and permeability-related studies have been performed. Despite numerous efforts, no antitubercular drug targeting MtbTMPK has reached the market or clinical trials, though some non-nucleoside inhibitors are in preclinical stages. As MtbTMPK is crucial for Mycobacterium tuberculosis survival and its inhibition effectively reduces the growth of the bacteria, making it a promising target for novel antitubercular drugs. In addition to thymidine-like core structures, several inhibitors with non-thymidine-like cores have also been developed as potent MtbTMPK inhibitors, opening new opportunities for future research to explore the uncharted chemical space of this target.

In the treatment of cancer and inflammation, small molecules become powerful therapeutic tools that provide new therapeutic approaches with improved efficacy and fewer side effects. This review offers a thorough summary of current developments in small-molecule drugs that target cancer and inflammatory pathways. Specifically, inhibition of phosphodiesterase-4 (PDE4) and COX receptors have demonstrated potential in the field of inflammation to help mitigate a variety of inflammatory disorders. We examine the structural design, mechanism of action, and therapeutic potential of innovative small compounds that inhibit or alter these pathways. Significant attention is placed on the dual anti-inflammatory and anti-cancer properties of these substances. The evaluation emphasizes preclinical and clinical data, revealing the most promising candidates under development. In summary, the precise manipulation of cellular signalling pathways by small compounds constitutes a dynamic domain with the capacity to revolutionize therapeutic approaches for inflammation and cancer. Ongoing investigation of these chemicals is essential for the advancement of safer and more efficacious therapies.