INTRODUCTION:Lysine-specific demethylase 1 (LSD1) is a key epigenetic enzyme relying on flavin adenine dinucleotide to regulate gene expression via histone H3 demethylation and non-histone substrate modification. Discovered in 2004, it overturned the view that histone modifications are irreversible. Abnormal LSD1 overexpression drives solid tumor and hematological malignancy initiation, progression, and drug resistance, making it a key oncology target. AREAS COVERED:This review discusses recent innovations in LSD1 inhibitor development, focusing on small-molecule patents published from 2022 to 2025. A systematic search of SciFinder, Derwent Innovation, and WIPO databases was conducted for this period. It categorizes these novel inhibitors into six classes and summarizes their structural features, biological data, design strategies and LSD1 interaction mechanisms. EXPERT OPINION:In recent years, LSD1 inhibitors have demonstrated structural diversification, innovative mechanisms, and expanded indications. Concurrently, breakthroughs have been achieved in optimizing structure, mechanism of action, dual-target strategies, selectivity and safety, and indications. Future efforts should focus on further validating dual-target strategies, and elucidating binding mechanisms to advance their application as a core targeted therapy in epigenetics for more malignant tumors therapy.

The application of machine learning (ML) in small-molecule drug discovery has expanded rapidly, garnering considerable attention in recent years. A thorough understanding of ML principles and their practical applications is increasingly essential for pharmacologists and drug researchers. Despite notable advancements, significant challenges persist, including limited data quality, difficulties in feature selection, and restricted model generalizability. This review systematically surveys the landscape of ML algorithms, categorizes them by model type, and highlights how various ML tools and techniques have been developed to address specific challenges at different stages of the drug discovery process.

Integrated computational-experimental platforms are promising for GPCR drug discovery, but systematically connecting high-resolution structural prediction with functional validation remains challenging. Here, we apply an integrated platform to discover a novel, potent antagonist targeting the P2Y14 receptor (P2Y14R), a key target in inflammatory diseases. Combining structure-based virtual screening, BPMD, all-atom molecular dynamics simulations, and cellular cAMP functional assays, our platform pinpointed Benfotiamine, an approved drug, as a nanomolar-potency P2Y14R antagonist (IC50 = 0.31 nM). Computational analyses indicated that Benfotiamine exerts a "conformational lock" to stabilize the inactive receptor and hinder Gi coupling. Subsequent CETSA and SPR experiments confirmed its direct binding to the target. Functionally, Benfotiamine exhibited therapeutic efficacy in murine models of dextran sulfate sodium-induced colitis and monosodium urate-induced gouty arthritis. Beyond presenting a promising repurposed anti-inflammatory agent, this study validates a modular and extensible computational-experimental integration platform that can be widely applied to expedite the discovery and mechanistic characterization of GPCR-targeted therapeutics.

Asthma is a chronic inflammatory airway disease characterized by barrier dysfunction and excessive inflammatory response. In this study, we identified that a traditional Chinese medicine Akebia quinate extract alleviated asthmatic phenotype in vivo. Transcriptomic analysis revealed that Akebia quinate extract associated with inflammatory response and airway epithelial barrier remodeling. Using network pharmacology screened the top four active ingredients from Akebia quinate and further evaluated their effects on inflammatory cytokines and airway barrier indicators. Among them, compound Calceolarioside B exhibited the most potent anti-inflammatory and barrier-protective activities. Pharmacodynamic validation confirmed that Calceolarioside B alone significantly ameliorated asthmatic features. The candidate target of Calceolarioside B was identified as P2Y6R using AI-assisted deep learning, virtual target fishing, and molecular dynamics simulations. In vitro binding assays validated the interaction between Calceolarioside B and P2Y6R. Furthermore, Calceolarioside B treatment failed to produce additional therapeutic effects in the P2Y6R knockout asthmatic mouse model, confirming that P2Y6R was the functionally relevant target of Calceolarioside B. Subsequent molecular docking and point mutation experiments identified LYS-25 as the effective binding site for Calceolarioside B and P2Y6R. Collectively, these findings demonstrate that Calceolarioside B alleviates asthma by targeting P2Y6R, providing a mechanistic basis for its therapeutic potential and a rationale for developing target-specific interventions.

Given the limited efficacy of existing therapies for metastatic colorectal cancer (mCRC), there is an urgent need for novel strategies. Prohibitin 1 (PHB1) is significantly upregulated in CRC, where it plays a critical role in oxidative phosphorylation (OXPHOS) to meet the heightened energy demands of rapid tumor growth and metastasis. Here, we discover that PHB1 interacts with NADH: ubiquinone oxidoreductase core subunit S1 (NDUFS1), a subunit of the OXPHOS complex, thereby modulating mitochondrial respiratory function. Based on these insights, we developed TD6, a highly potent and selective small-molecule inhibitor of PHB1. In a mouse model of colorectal cancer pulmonary metastasis (CRPM), TD6 treatment significantly prolonged animal survival. Mechanistically, TD6 binds to PHB1 and induces a conformational change in the PHB complex, which reduces PHB-mediated stabilization of NDUFS1. Disruption of the PHB-NDUFS1 interaction promotes NDUFS1 degradation via the lysosomal pathway, leading to impaired activity of mitochondrial complex I (MCI) and reduced OXPHOS function. In summary, PHB1 maintains MCI stability and OXPHOS activity through its interaction with NDUFS1. By targeting PHB1, TD6 effectively disrupts this regulatory axis, demonstrating therapeutic potential against CRPM. This study presents a novel drug candidate and a theoretical foundation for PHB1-based interventions targeting cancer energy metabolism.

The P2Y14 receptor (P2Y14R) is a G protein-coupled receptor (GPCR) that can be activated by the extracellular nucleotide uridine diphosphate glucose (UDPG). It performs crucial regulatory roles in diverse pathophysiological contexts, such as immune modulation, inflammatory responses, tumor progression, and metabolic disorders. Therefore, it represents a highly attractive therapeutic target. This review elucidates the signal transduction mechanism of P2Y14R and its pathological functions in conditions such as gouty arthritis (GA) and neuropathic pain (NP). Meanwhile, P2Y14R inhibitors based on multiple drug discovery strategies are also comprehensively summarized. Furthermore, this review analyzes the key challenges currently faced in inhibitors research and development. By integrating the latest reported crystal structure of P2Y14R, it looks forward to the prospects of precise drug design based on structure and clinical translation. This provides a theoretical basis and innovative direction for the future development of P2Y14R-targeted therapeutic drugs.

Parallel activation of the calcitonin receptor (CTR) and amylin receptor (AMYR) is considered a more effective weight-loss strategy. Although the novel dual amylin and calcitonin receptor agonist (DACRA), petrelintide, is currently undergoing phase II clinical trials, its agonistic activity remains insufficient compared with natural agonists. Further optimization of the agonistic capabilities of petrelintide is an attractive strategy for developing DACRAs. Due to the lack of structure-activity relationship (SAR) and target binding information, a step-by-step process involving three rounds of modifications was performed guided by structure-based drug design and molecular dynamics (MD) simulations. Two successful methylation strategies led to the identification of the more efficient novel DACRA, BGM1812, with excellent performance in terms of half-life, stability, and solubility. In both in vivo and in vitro studies, BGM1812 showed significantly enhanced efficacy. This finding provides valuable insights into the SAR of petrelintide and highlights the potential of BGM1812 as a promising obesity drug candidate.

G protein-coupled receptors (GPCRs) can transmit signals via G protein-dependent or independent pathways due to the conformational changes of receptors and ligands, which is called biased signaling. This concept posits that ligands can selectively activate a specific signaling pathway after receptor activation, facilitating downstream signaling along a preferred pathway. Biased agonism enables the development of ligands that prioritize therapeutic signaling pathways while mitigating on-target undesired effects. As a class of GPCRs located on the surface of cell membranes, the discovery and clinical implementation of adenosine and P2Y receptors purinergic signaling modulators have progressed dramatically. However, many preclinical drug candidates targeting purinergic receptors have failed in clinical trials due to limited efficacy and/or severe on-target undesired effects. To overcome the key barriers typically encountered when transitioning ligands into the clinic, the renewed impetus has focused on the modulation of purinergic receptor function by exogenous agonists/antagonists and allosteric modulators to exploit biased agonism. This article provides a brief overview of the research progress on the mechanism of purinergic biased signal transduction from the conformational changes of purinergic GPCRs and biased ligands primarily, and highlights therapeutically relevant biased agonism at purinergic receptors.

Targeted radionuclide therapy represents a promising therapeutic method for treating cancer. However, currently approved radioligands still require improvement in terms of tumor uptake and retention. This study employed molecular simulation to design a novel radioligand, designated PSMA-MAL-5, which covalently binds to the prostate-specific membrane antigen (PSMA). This ligand can be efficiently radiolabeled with the beta emitter (177Lu) and the alpha emitter (225Ac) and exhibits a high level of radiostability. Autoradiography confirmed that 177Lu-PSMA-MAL-5 binds covalently to PSMA. In vivo experiments demonstrated that the radioligand can effectively target PSMA-positive tumors, with an area under the curve of tumor uptake higher than that observed for 177Lu-PSMA-617 (2517 ± 499 h %ID/cm3 vs 575 ± 75 h %ID/cm3). Tumor inhibition studies indicated that the radioligand exhibited a notable tumor inhibitory effect on tumor growth, showing promise as a tool for targeted radionuclide therapy of PSMA-positive prostate cancer.

Introduction The P2Y14 receptor (P2Y14R), a Gi-coupled receptor activated by UDP-glucose, plays a critical role in inflammatory responses and immune regulation. Existing P2Y14R antagonists face limitations such as poor bioavailability and structural homogeneity, hindering therapeutic development for inflammatory bowel disease (IBD). Drug repurposing offers a promising strategy to bypass traditional drug discovery challenges by leveraging approved drugs with established safety profiles. Objectives This study aimed to computationally identify FDA-approved or experimental drugs as novel P2Y14R antagonists and validate their therapeutic potential for IBD treatment. Methods A multi-step computational pipeline integrated structure-based virtual screening (SBVS) of DrugBank drug compounds, molecular docking (Glide XP/AutoDock Vina), molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations. Top candidates underwent in vitro P2Y14R antagonism assays and cytotoxicity testing. In vivo efficacy was evaluated in a DSS-induced murine colitis model. Results Chloramphenicol succinate (DB07565), an antibiotic, emerged as a potent P2Y14R antagonist with nanomolar efficacy (IC50 = 1.585 nM) and minimal cytotoxicity. MD simulations revealed strong interactions with conserved residues (K77, Y102, H184, K277), yielding a binding affinity (ΔGbind = -54.04 kcal/mol) superior to reference compounds. In vivo, DB07565 alleviated colitis symptoms, reduced colon shortening, and restored gut barrier integrity by enhancing tight junction protein expression (Claudin-1, ZO-1, Occludin). Conclusion This study demonstrates that computational repurposing successfully identifies DB07565 as a high-affinity P2Y14R antagonist with therapeutic efficacy in IBD. Its established safety, oral stability, and optimized ADME/T properties position it as a clinically translatable candidate, underscoring the value of integrating SBVS and drug repurposing for accelerating anti-inflammatory drug discovery.

Depression is a common mental disorder with high economic burden, characterized by high disability and mortality rates. The etiology of depression remains unclear to date, and there are various hypotheses regarding the pathogenesis of depression in clinical practice, including the monoamine neurotransmitter hypothesis, the hypothalamic–pituitary–adrenal (HPA) axis dysregulation hypothesis, the inflammatory cytokine hypothesis, and the neurotrophic factor hypothesis. These theories offer specific directional aid in the clinical management of individuals suffering from depression. Medicinal intervention stands as a critical approach within the spectrum of depression treatments, and this article reviews the specific mechanisms of different hypotheses on the pathogenesis of depression in recent years, as well as the research progress on related therapeutic drugs.

The P2Y14 purinergic receptor (P2Y14R) plays a crucial role in the progression of liver fibrosis, and selective inhibition of this receptor has emerged as a promising therapeutic approach. In this study, an integrative computational pipeline identified a unique and highly flexible binding pocket within P2Y14R, which is divided into two quasi-symmetrical subdomains. Leveraging this structural feature, we designed and synthesized two novel families of inhibitors based on benzoxazole-urea and benzoxazole-squaramide scaffolds. The lead compound, 47 (HDB-1), demonstrates exceptional potency (IC50 = 0.026 nM) and superior metabolic stability. HDB-1 exhibited antihepatic fibrosis activity both in vivo and in vitro. Mechanistically, HDB-1 inhibits P2Y14R-mediated signaling by suppressing the PKA/Raf1/MEK/ERK cascade, thereby preventing the activation of hepatic stellate cells-the central pathological event in fibrosis development. Taken together, HDB-1 represents a novel and potent P2Y14R inhibitor with strong potential as an available therapeutic for liver fibrosis driven by dysregulated P2Y14R signaling.

INTRODUCTION:P2Y12 receptor (P2Y12R) is a G protein-coupled receptor that plays a crucial role in regulating platelet activation and aggregation. P2Y12R is involved in various processes such as renal fibrosis, cancer, ischemic disease, and related complications, making it an appealing target for therapeutic interventions. Over the past decade, the discovery and development of P2Y12R antagonists have significantly advanced, offering novel treatment options that improve clinical outcomes. AREAS COVERED:This review covers P2Y12R antagonists reported in patents issued in the online databases of the World Intellectual Property Organization and the European Patent Office from 2019 to 2024. This review introduces the development of existing antagonists and evaluates the therapeutic potential of these compounds. EXPERT OPINION:Reversible P2Y12R antagonists offer a potentially safer alternative to the currently dominant irreversible antagonists on the market, as they allow for more controlled platelet inhibition and can reduce the toxicity and adverse effects associated with conventional drugs. Importantly, the integration of computational drug design and molecular docking studies in the discovery and optimization of P2Y12R antagonists represents a significant advancement in precision medicine. This not only provides valuable structural scaffolds but also stimulates novel ideas for developing promising drugs that are both safe and efficacious.

Identifying molecular targets of physiologically active organic compounds remains a major challenge in contemporary biomedical research and drug discovery. In recent years, the development of activity-based protein profiling (ABPP) techniques has proven to be superior to classical molecular target identification methods. ABPP can be classified into activity-based probes (AcBPs) and affinity-based probes (AfBPs). AfBPs bind to target proteins through reversible non-covalent interactions, thus minimizing the impact on the natural biological functions of the protein. The development of AfBPs has great potential for studying drug targets, optimizing drugs, and improving therapeutic efficacy. As a result, there has been a dramatic increase in research and development focused on affinity probes with the use of a wide range of AfBPs such as biotin probes, FITC probes, BRET probes, and radiolabeled probes. This tutorial describes the process of designing and synthesizing different types of AfBPs from biologically active compounds, and then utilizing the probes to identify the target proteins. It also provides insights for subsequent drug discovery and development.

INTRODUCTION:Psoriasis is a prevalent and widespread chronic immune disease and i s impacted by several variables. Although various medicines with diverse modes of operation have been licensed for the medical management of psoriasis, the ongoing investigation into its pathophysiological mechanisms, along with challenges related to administration and cost, has led to the increasing preference for new small molecule medications, namely janus kinase (JAK) and phosphodiesterase 4 (PDE4) inhibitors, in systemic therapy research. AREAS COVERED:This review takes a medicinal chemistry perspective to comprehensively explore the development as psoriasis therapy targets for small molecule inhibitors of JAK and PDE4. We describe the chemical space explored by medicinal chemists from 2010 to 2024, with particular emphasis on the importance of inhibitors with diverse scaffolds in studies of selectivity, potency and binding modes. EXPERT OPINION:Advancements in psoriasis treatment have shifted focus toward small-molecule drugs, such as JAK and PDE4 inhibitors, which offer advantages over biologics, including oral administration, improved cost-effectiveness, and reduced immunogenicity. Structural optimization based on receptor proteins and combination therapies further enhance drug performance and safety. Preclinical and clinical studies indicate that these strategies hold promise for developing more targeted, safer, and more effective treatments for psoriasis.

Background and Aims Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis. Methods The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists. Results The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cβ/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified. Conclusions Macrophage P2Y6R regulates phospholipase Cβ/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate.

BackgroundPurinergic P2 receptors, which can be divided into ionotropic P2X receptors and metabotropic P2Y receptors, mediate cellular signal transduction of purine or pyrimidine nucleoside triphosphates and diphosphate. Based on the wide expression of purinergic P2 receptors in tissues and organs, their significance in homeostatic maintenance, metabolism, nociceptive transmission, and other physiological processes is becoming increasingly evident, suggesting that targeting purinergic P2 receptors to regulate biological functions and signal transmission holds significant promise for disease treatment.Aim of reviewThis review highlights the detailed mechanisms by which purinergic P2 receptors engage in physiological and pathological progress, as well as providing prospective strategies for discovering clinical drug candidates.Key scientific concepts of reviewThe purinergic P2 receptors regulate complex signaling and molecular mechanisms in nervous system, digestive system, immune system and as a result, controlling physical health states and disease progression. There has been a significant rise in research and development focused on purinergic P2 receptors, contributing to an increased number of drug candidates in clinical trials. A few influential pioneers have laid the foundation for advancements in the evaluation, development, and of novel purinergic P2 receptors modulators, including agonists, antagonists, pharmaceutical compositions and combination strategies, despite the different scaffolds of these drug candidates. These advancements hold great potential for improving therapeutic outcomes by specifically targeting purinergic P2 receptors.

Purinergic signaling plays a causal role in the modulation of immune inflammatory response in the course of psoriasis, but its regulatory mechanism remains unclear. As a member of purinoceptors, P2Y6R mainly distributed in macrophages was significantly up-expressed in skin lesions from patients with psoriasis in the present study. Here, the severity of psoriasis was alleviated in imiquimod-treated mice with macrophages conditional knockout of P2Y6R, while the cell-chat algorithm showed there was a correlation between macrophage P2Y6R and Th1 cells mediated by IL-27. Mechanistically, P2Y6R enhanced PLCβ/p-PKC/MAPK activation to induce IL-27 release dependently, which subsequently regulated the differentiation of Th1 cells, leading to erythematous and scaly plaques of psoriasis. Interestingly, we developed a novel P2Y6R inhibitor FS-6, which bonds with the ARG266 side chain of P2Y6R, exhibited remarkable anti-psoriasis effects targeting P2Y6R. Our study provides insights into the role of P2Y6R in the pathogenesis of psoriasis and suggests its potential as a target for the development of therapeutic interventions. A novel P2Y6R inhibitor FS-6 could be developed as an anti-psoriasis drug candidate for the clinic.