Application of artificial intelligence in drug design: A review.

Artificial intelligence (AI) is a field of computer science that involves acquiring information, developing rule bases, and mimicking human behaviour. The fundamental concept behind AI is to create intelligent computer systems that can operate with minimal human intervention or without any intervention at all. These rule-based systems are developed using various machine learning and deep learning models, enabling them to solve complex problems. AI is integrated with these models to learn, understand, and analyse provided data. The rapid advancement of Artificial Intelligence (AI) is reshaping numerous industries, with the pharmaceutical sector experiencing a notable transformation. AI is increasingly being employed to automate, optimize, and personalize various facets of the pharmaceutical industry, particularly in pharmacological research. Traditional drug development methods areknown for being time-consuming, expensive, and less efficient, often taking around a decade and costing billions of dollars. The integration of artificial intelligence (AI) techniques addresses these challenges by enabling the examination of compounds with desired properties from a vast pool of input drugs. Furthermore, it plays a crucial role in drug screening by predicting toxicity, bioactivity, ADME properties (absorption, distribution, metabolism, and excretion), physicochemical properties, and more. AI enhances the drug design process by improving the efficiency and accuracy of predicting drug behaviour, interactions, and properties. These approaches further significantly improve the precision of drug discovery processes and decrease clinical trial costs leading to the development of more effective drugs.

Inhibitors of the Structural and Nonstructural Proteins of Alphaviruses.

The Alphavirus genus includes viruses that cause encephalitis due to neuroinvasion and viruses that cause arthritis due to acute and chronic inflammation. There is no approved therapeutic for alphavirus infections, but significant efforts are ongoing, more so in recent years, to develop vaccines and therapeutics for alphavirus infections. This review article highlights some of the major advances made so far to identify small molecules that can selectively target the structural and the nonstructural proteins in alphaviruses with the expectation that persistent investigation of an increasingly expanding chemical space through a variety of structure-based design and high-throughput screening strategies will yield candidate drugs for clinical studies. While most of the works discussed are still in the early discovery to lead optimization stages, promising avenues remain for drug development against this family of viruses.

Investigating Photoactive Antimicrobials as Alternatives (or Adjuncts) to Traditional Therapy.

Photodynamic therapy (PDT) is an established therapy used for the treatment of cutaneous skin cancers and other non-infective ailments. There has been recent interest in the opportunity to use aPDT (antimicrobial PDT) to treat skin and soft tissue infections. PDT utilizes photosensitizers that infiltrate all cells and "sensitize" them to a given wavelength of light. The photosensitizer is simply highly absorbent to a given wavelength of light and when excited will produce, in the presence of oxygen, damaging oxygen radicals and singlet oxygen. Bacterial cells are comparatively poor at combatting oxidative stress when compared with human cells therefore a degree of selective toxicity can be achieved with aPDT.In this chapter, we outline methodologies for testing aPDT in vitro using standard lab equipment.

BACE1 inhibitor drugs for the treatment of Alzheimer's disease: Lessons learned, challenges to overcome, and future prospects†.

Alzheimer's disease (AD), first diagnosed over a century ago, remains one of the major healthcare crises around the globe. Currently, there is no cure or effective treatment. The majority of drug development efforts to date have targeted reduction of amyloid-ß peptide (Aß). Drug development through inhibition of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), resulted in promising early clinical studies. However, nearly all small molecule BACE1 inhibitor drugs failed to live up to expectations in later phase clinical trials, due to toxicity and efficacy issues. This commentary aims to provide a brief review of over two decades of BACE1 inhibitor drug development challenges and efforts for treatment of AD and prospects of future BACE1-based drugs.

G protein-coupled receptors and traditional Chinese medicine: new thinks for the development of traditional Chinese medicine.

G protein-coupled receptors (GPCRs) widely exist in vivo and participate in many physiological processes, thus emerging as important targets for drug development. Approximately 30% of the Food and Drug Administration (FDA)-approved drugs target GPCRs. To date, the 'one disease, one target, one molecule' strategy no longer meets the demands of drug development. Meanwhile, small-molecule drugs account for 60% of FDA-approved drugs. Traditional Chinese medicine (TCM) has garnered widespread attention for its unique theoretical system and treatment methods. TCM involves multiple components, targets and pathways. Centered on GPCRs and TCM, this paper discusses the similarities and differences between TCM and GPCRs from the perspectives of syndrome of TCM, the consistency of TCM's multi-component and multi-target approaches and the potential of GPCRs and TCM in the development of novel drugs. A novel strategy, 'simultaneous screening of drugs and targets', was proposed and applied to the study of GPCRs. We combine GPCRs with TCM to facilitate the modernisation of TCM, provide valuable insights into the rational application of TCM and facilitate the research and development of novel drugs. This study offers theoretical support for the modernisation of TCM and introduces novel ideas for development of safe and effective drugs.

A comprehensive review of 3D cancer models for drug screening and translational research.

The 3D cancer models fill the discovery gap of 2D cancer models and play an important role in cancer research. In addition to cancer cells, a range of other factors include the stroma, density and composition of extracellular matrix, cancer-associated immune cells (e.g., cancer-associated fibroblasts cancer cell-stroma interactions and subsequent interactions, and a number of other factors (e.g., tumor vasculature and tumor-like microenvironment in vivo) has been widely ignored in the 2D concept of culture. Despite this knowledge, the continued use of monolayer cell culture methods has led to the failure of a series of clinical trials. This review discusses the immense importance of tumor microenvironment (TME) recapitulation in cancer research, prioritizing the individual roles of TME elements in cancer histopathology. The TME provided by the 3D model fulfills the requirements of in vivo spatiotemporal arrangement, components, and is helpful in analyzing various different aspects of drug sensitivity in preclinical and clinical trials, some of which are discussed here. Furthermore, it discusses models for the co-assembly of different TME elements in vitro and focuses on their synergistic function and responsiveness as tumors. Furthermore, this review broadly describes of a handful of recently developed 3D models whose main focus is limited to drug development and their screening and/or the impact of this approach in preclinical and translational research.

Trastuzumab-deruxtecan in solid tumors with HER2 alterations: from early phase development to the first agnostic approval of an antibody-drug conjugate.

INTRODUCTION: Antibody-drug conjugates (ADCs) represent a revolutionary approach in the systemic treatment for both solid and hematologic tumors. Constituted by an antibody, a cytotoxic payload, and a linker, ADCs aim to selectively deliver cytotoxic agents to tumors while sparing normal tissues. Various ADCs have been tested and approved for multiple solid tumors so far, but if there is one that had a major impact on clinical practice, this is Trastuzumab-deruxtecan (T-DXd). Notably, T-DXd was approved for HER2-positive and HER2-low metastatic breast cancer (MBC), HER2-positive gastric cancer (GC), HER2-mutant non-small cell lung cancer (NSCLC) and HER2 3+ solid tumors. Moreover, it received Breakthrough Therapy Designation for HER2-positive colorectal cancer (CRC). AREAS COVERED: We review preclinical and clinical data of T-DXd, focusing on early-phase ongoing trials exploring combination therapies to enhance the activity of T-DXd in HER2-expressing solid tumors. EXPERT OPINION: The clinical use of T-DXd still raises questions about selection of patients, treatment duration, prioritization over other approved ADCs, and management of resistance. Concerns regarding the toxicity of T-DXd remain, particularly with combinations involving potentially toxic drugs. Advancements in biomarker identification and combination therapies offer promising avenues to enhance efficacy and overcome resistance to T-DXd, ultimately improving outcomes for patients with cancer.

Current status and perspective on molecular targets and therapeutic intervention strategy in hepatic ischemia-reperfusion injury.

Hepatic ischemia‒reperfusion injury (HIRI) is a common and inevitable complication of hepatic trauma, liver resection, or liver transplantation. It contributes to postoperative organ failure or tissue rejection, eventually affecting patient prognosis and overall survival. The pathological mechanism of HIRI is highly complex and has not yet been fully elucidated. The proposed underlying mechanisms include mitochondrial damage, oxidative stress imbalance, abnormal cell death, immune cell hyperactivation, intracellular inflammatory disorders and other complex events. In addition to serious clinical limitations, available antagonistic drugs and specific treatment regimens are still lacking. Therefore, there is an urgent need to not only clarify the exact etiology of HIRI but also reveal the possible reactions and bottlenecks of existing drugs, helping to reduce morbidity and shorten hospitalizations. We analyzed the possible underlying mechanism of HIRI, discussed various outcomes among different animal models and explored neglected potential therapeutic strategies for HIRI treatment. By thoroughly reviewing and analyzing the literature on HIRI, we gained a comprehensive understanding of the current research status in related fields and identified valuable references for future clinical and scientific investigations.

Methods for negating the impact of zinc contamination to allow characterization of positive allosteric modulators of glycine receptors.

Zinc is a ubiquitous contaminant in many buffers, purified products and common labware that has previously been suggested to impact on the results of functional GlyR studies and may inadvertently cause the effectiveness of some GlyR modulators to be over-estimated. This could greatly impact the assessment of potential drug-candidates and contribute to the reduced effectiveness of compounds that reach clinical stages. This is especially true for GlyR modulators being developed for pain therapeutics due to the changes in spinal zinc concentrations that have been observed during chronic pain conditions. In this study we use two-electrode voltage clamp electrophysiology to evaluate the metal chelators tricine and Ca-EDTA, and show that tricine produces inhibitory effects at GlyRα1 that are not mediated by zinc. We also utilized the zinc insensitive W170S mutation as a tool to validate metal chelators and confirm that zinc contamination has not impacted the examination of lipid modulators previously developed by our lab. This study helps to further develop methods to negate the impact of contaminating zinc in functional studies of GlyRs which should be incorporated into future studies that seek to characterize the activity of novel modulators at GlyRs.

The anti-tubercular callyaerins target the Mycobacterium tuberculosis-specific non-essential membrane protein Rv2113.

Spread of antimicrobial resistances urges a need for new drugs against Mycobacterium tuberculosis (Mtb) with mechanisms differing from current antibiotics. Previously, callyaerins were identified as promising anti-tubercular agents, representing a class of hydrophobic cyclopeptides with an unusual (Z)-2,3-di-aminoacrylamide unit. Here, we investigated the molecular mechanisms underlying their antimycobacterial properties. Structure-activity relationship studies enabled the identification of structural determinants relevant for antibacterial activity. Callyaerins are bacteriostatics selectively active against Mtb, including extensively drug-resistant strains, with minimal cytotoxicity against human cells and promising intracellular activity. By combining mutant screens and various chemical proteomics approaches, we showed that callyaerins target the non-essential, Mtb-specific membrane protein Rv2113, triggering a complex dysregulation of the proteome, characterized by global downregulation of lipid biosynthesis, cell division, DNA repair, and replication. Our study thus identifies Rv2113 as a previously undescribed Mtb-specific drug target and demonstrates that also non-essential proteins may represent efficacious targets for antimycobacterial drugs.

Evolution of Drug Development and Regulatory Affairs: The Demonstrated Power of Artificial Intelligence.

PURPOSE: Artificial intelligence (AI) refers to technology capable of mimicking human cognitive functions and has important applications across all sectors and industries, including drug development. This has considerable implications for the regulation of drug development processes, as it is expected to transform both the way drugs are brought to market and the systems through which this process is controlled. There is currently insufficient evidence in published literature of the real-world applications of AI. Therefore, this narrative review investigated, collated, and elucidated the applications of AI in drug development and its regulatory processes. METHODS: A narrative review was conducted to ascertain the role of AI in streamlining drug development and regulatory processes. FINDINGS: The findings of this review revealed that machine learning or deep learning, natural language processing, and robotic process automation were favored applications of AI. Each of them had considerable implications on the operations they were intended to support. Overall, the AI tools facilitated access and provided manageability of information for decision-making across the drug development lifecycle. However, the findings also indicate that additional work is required by regulatory authorities to set out appropriate guidance on applications of the technology, which has critical implications for safety, regulatory process workflow and product development costs. IMPLICATIONS: AI has adequately proven its utility in drug development, prompting further investigations into the translational value of its utility based on cost and time saved for the delivery of essential drugs.

A new tau dephosphorylation-targeting chimera for the treatment of tauopathies.

Abnormal accumulation of hyperphosphorylated tau protein plays a pivotal role in a collection of neurodegenerative diseases named tauopathies, including Alzheimer's disease (AD). We have recently conceptualized the design of hetero-bifunctional chimeras for selectively promoting the proximity between tau and phosphatase, thus specifically facilitating tau dephosphorylation and removal. Here, we sought to optimize the construction of tau dephosphorylating-targeting chimera (DEPTAC) and obtained a new chimera D14, which had high efficiency in reducing tau phosphorylation both in cell and tauopathy mouse models, while showing limited cytotoxicity. Moreover, D14 ameliorated neurodegeneration in primary cultured hippocampal neurons treated with toxic tau-K18 fragments, and improved cognitive functions of tauopathy mice. These results suggested D14 as a cost-effective drug candidate for the treatment of tauopathies.

Application of physiologically based pharmacokinetic modeling of novel drugs approved by the U.S. food and drug administration.

Physiologically based pharmacokinetic (PBPK) models which can leverage preclinical data to predict the pharmacokinetic properties of drugs rapidly became an essential tool to improve the efficiency and quality of novel drug development. In this review, by searching the Application Review Files in Drugs@FDA, we analyzed the current application of PBPK models in novel drugs approved by the U.S. Food and Drug Administration (FDA) in the past five years. According to the results, 243 novel drugs were approved by the FDA from 2019 to 2023. During this period, 74 Application Review Files of novel drugs approved by the FDA that used PBPK models. PBPK models were used in various areas, including drug-drug interactions (DDI), organ impairment (OI) patients, pediatrics, drug-gene interaction (DGI), disease impact, and food effects. DDI was the most widely used area of PBPK models for novel drugs, accounting for 74.2 % of the total. Software platforms with graphical user interfaces (GUI) have reduced the difficulty of PBPK modeling, and Simcyp was the most popular software platform among applicants, with a usage rate of 80.5 %. Despite its challenges, PBPK has demonstrated its potential in novel drug development, and a growing number of successful cases provide experience learned for researchers in the industry.

Did pediatric drug development advance epilepsy treatment in young patients? It is time for new research goals.

Modern drugs have changed epilepsy, which affects people of all ages. However, for young people with epilepsy, the framework of drug development has stalled. In the wake of the thalidomide catastrophe, the misconception emerged that for people < 18 years of age drugs, including antiseizure medications (ASMs), need separate proof of efficacy and safety, overall called "pediatric drug development". For ASMs, this has changed to some degree. Authorities now accept that ASMs are effective in < 18 years as well, but they still require "extrapolation of efficacy," as if minors were another species. As a result, some of the pediatric clinical epilepsy research over the past decades was unnecessary. Even more importantly, this has hampered research on meaningful research goals. We do not need to confirm that ASMs work before as they do after the 18th birthday. Instead, we need to learn how to prevent brain damage in young patients by preventing seizures and optimize ASMs' uses. Herein we discuss how to proceed in this endeavor.

Visualization analysis of research hotspots and trends on gastrointestinal tumor organoids.

BACKGROUND: Gastrointestinal tumor organoids serve as an effective model for simulating cancer in vitro and have been applied in basic biology and preclinical research. Despite over a decade of development and increasing research achievements in this field, a systematic and comprehensive analysis of the research hotspots and future trends is lacking. AIM: To address this problem by employing bibliometric tools to explore the publication years, countries/regions, institutions, journals, authors, keywords, and references in this field. METHODS: The literature was collected from Web of Science databases. CiteSpace-6.2R4, a widely used bibliometric analysis software package, was used for institutional analysis and reference burst analysis. VOSviewer 1.6.19 was used for journal co-citation analysis, author co-authorship and co-citation analysis. The 'online platform for bibliometric analysis (https://bibliometric.com/app)' was used to assess the total number of publications and the cooperation relationships between countries. Finally, we employed the bibliometric R software package (version R.4.3.1) in R-studio, for a comprehensive scientific analysis of the literature. RESULTS: Our analysis included a total of 1466 publications, revealing a significant yearly increase in articles on the study of gastrointestinal tumor organoids. The United States (n = 393) and Helmholtz Association (n = 93) have emerged as the leading countries and institutions, respectively, in this field, with Hans Clevers and Toshiro Sato being the most contributing authors. The most influential journal in this field is Gastroenterology. The most impactful reference is "Long term expansion of epithelial organs from human colon, adenoma, adenocarcinoma, and Barrett's epithelium". Keywords analysis and citation burst analysis indicate that precision medicine, disease modeling, drug development and screening, and regenerative medicine are the most cutting-edge directions. These focal points were further detailed based on the literature. CONCLUSION: This bibliometric study offers an objective and quantitative analysis of the research in this field, which can be considered as an important guide for next scientific research.

Prediction and analysis of components and functions of Ixeris chinensis based on network pharmacology and molecular docking.

Background: It is reported that the Ixeris chinensis has high medicinal value, but there are few reports about its potential molecular mechanism. We used a network pharmacology approach to predict the active ingredients, targets of action and possible interventions in diseases of Ixeris chinensis. Methods: We employed various databases and software to predict the active ingredients, target genes, protein interactions, signaling pathways, network diagrams, and molecular docking of Ixeris chinensis. Simultaneously, we searched multiple Chinese and English databases and conducted meta-analyses of five randomized controlled trials. Results: The analysis results revealed 12 effective components, including apigenin ß-sitosterol, baicalin, baicalein, and luteolin; and selected 40 key targets, including AKT1, TNF, EGFR, ESR1, SRC, among others. GO analysis generated 225 biological processes, 39 cellular components, and 65 molecular functions; KEGG analysis revealed 103 signaling pathways. Molecular docking results indicated that the main active components of Ixeris chinensis can bind well with key targets. Five randomized controlled trials were included. Meta-analysis showed that Ixeris extract can effectively reduce animal blood lipid levels. Conclusion: This study revealed the main active ingredients and key targets of Ixeris chinensis, analyzed the signaling pathways of potential targets, conducted disease prediction, and performed molecular docking prediction, providing a basis for research on the pathways of Ixeris treatment for related diseases and subsequent new drug development.

Intestinal biofilms: pathophysiological relevance, host defense, and therapeutic opportunities.

SUMMARYThe human intestinal tract harbors a profound variety of microorganisms that live in symbiosis with the host and each other. It is a complex and highly dynamic environment whose homeostasis directly relates to human health. Dysbiosis of the gut microbiota and polymicrobial biofilms have been associated with gastrointestinal diseases, including irritable bowel syndrome, inflammatory bowel diseases, and colorectal cancers. This review covers the molecular composition and organization of intestinal biofilms, mechanistic aspects of biofilm signaling networks for bacterial communication and behavior, and synergistic effects in polymicrobial biofilms. It further describes the clinical relevance and diseases associated with gut biofilms, the role of biofilms in antimicrobial resistance, and the intestinal host defense system and therapeutic strategies counteracting biofilms. Taken together, this review summarizes the latest knowledge and research on intestinal biofilms and their role in gut disorders and provides directions toward the development of biofilm-specific treatments.

Unlocking epigenetics for precision treatment of Ewing's sarcoma.

Ewing's sarcoma (EWS) is a highly aggressive malignant bone tumor primarily affecting adolescents and young adults. Despite the efficacy of chemoradiotherapy in some cases, the cure rate for patients with metastatic and recurrent disease remains low. Therefore, there is an urgent need for innovative therapeutic approaches to address the challenges associated with EWS treatment. Epigenetic regulation, a crucial factor in physiological processes, plays a significant role in controlling cell proliferation, maintaining gene integrity, and regulating transcription. Recent studies highlight the importance of abnormal epigenetic regulation in the initiation and progression of EWS. A comprehensive understanding of the intricate interactions between EWS and aberrant epigenetic regulation is essential for advancing clinical drug development. This review aims to provide a comprehensive overview of both epigenetic targets implicated in EWS, integrating various therapeutic modalities to offer innovative perspectives for the clinical diagnosis and treatment of EWS.

Strain-Release-Driven Modular Synthesis of Oxetane-Based Amide Bioisosteres: Concise, Robust and Scalable Approach.

Amide bioisoterism is a widely used strategy in drug development to fine-tune physicochemical, pharmacokinetic, and metabolic properties, eliminate toxicity and gain intellectual property rights in uncharted chemical space. Of these, oxetane-amines offer particularly exciting possibilities as bioisosteres, although they are less frequently investigated than warranted due to the lack of simple and widely applicable synthetic methods. Herein, we report a two-step, practical, modular, robust, and scalable method for the construction of oxetane-containing amide bioisosteres that relies on the readily available oxetan-3-one. This operationally simple procedure exploits the enhanced reactivity of the keto group of the commercially available oxetan-3-one to form amine-benzotriazole intermediates, which springloaded adducts are then reacted with various aliphatic and aromatic organometallic reagents under mild conditions to afford various amino-oxetanes in good to high yields. The simplicity and broad applicability of the method greatly facilitates the synthesis of derivatives that were previously difficult or impossible to produce. The usefulness of this method in the field medicinal chemistry was also demonstrated by eliminating the well-known metabolic problem of ketoconazole.