分类： 药物科学 >> 药代动力学 提交时间： 2025-01-16
摘要： Background: BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the tranObjective: This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, in vitro and in vivo metabolic profile of BPI-460372.Methods: The CYP phenotyping and metabolic stability were assessed by measuring the depletion of substrate. The metabolic profile in hepatocytes, rats, and dog plasma was analyzed using ultra-high performance liquid chromatography combined with orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).Results: BPI-460372 was mainly metabolized by CYP2D6, CYP3A4, and CYP1A2. BPI-460372 exhibited low clearance in human, monkey, and rat hepatocytes, while moderate clearance in dog and mouse hepatocytes. A total of 10 metabolites were identified in five species of hepatocytes, and no human unique metabolite was detected. In rat plasma and dog plasma, the primary metabolites were M407 (BPI-460430) and M423 (BPI-460456), respectively. The two metabolites were quantitatively determined in rat and dog plasma in pharmacokinetic and toxicological studies. The major metabolic sites were 2-fluoro acrylamide, and major metabolic pathways in hepatocytes, rats, and dog plasma involved oxidative defluorination, hydration, glutathione conjugation, hydrolysis, cysteine conjugation and N-acetyl cysteine conjugation. β-lyase pathway contribute to the metabolism of BPI-460372 in rats to a certain degree.Conclusion: This study elucidated the metabolism of BPI-460372 and provided a basis for pharmacokinetic and toxicological species selection, human pharmacokinetics prediction, clinical co-administration limitations, and possible metabolic pathways in humans.
分类： 药物科学 >> 药物设计 提交时间： 2024-12-30
Wang, Xudong
Xiong, Liwei
Zhu, Ying
Liu, Sixiu
Zhao, Wenfeng
Wu, Xinyuan
Seydimemet, Mengnisa
Li, Linjie
Ding, Peiqi
Lin, Xian
Liu, Jiaxiang
Wang, Xuan
Duan, Zhiqiang
Lu, Weiwei
Suo, Yanrui
Cui, Mengqing
Yue, Jinfeng
Jin, Rui
Zheng, Mingyue
Xu, Yechun
摘要： The COVID-19 pandemic, exacerbated by persistent viral mutations, underscored the urgent need for diverse inhibitors targeting multiple viral proteins. In this study, we utilized covalent DNA-encoded libraries to discover innovative triazine-based covalent inhibitors for the 3-chymotrypsin-like protease (3CLpro, Nsp5) and the papain-like protease (PLpro) domains of Nsp3, as well as novel non-nucleoside covalent inhibitors for the nonstructural protein 12 (Nsp12, RdRp). Optimization through molecular docking and medicinal chemistry led to the development of LU9, a nonpeptide 3CLpro inhibitor with an IC50 of 0.34 mu M, and LU10, whose crystal structure showed a distinct binding mode within the 3CLpro active site. The X-ray cocrystal structure of SARS-CoV-2 PLpro in complex with XD5 uncovered a previously unexplored binding site adjacent to the catalytic pocket. Additionally, a non-nucleoside covalent Nsp12 inhibitor XJ5 achieved a potency of 0.12 mu M following comprehensive structure-activity relationship analysis and optimization. Molecular dynamics revealed a potential binding mode. These compounds offer valuable chemical probes for target validation and represent promising candidates for the development of SARS-CoV-2 antiviral therapies.
分类： 药物科学 >> 药物化学 提交时间： 2024-12-30
Ma, Shengzhou
Zhang, Pengfei
Ye, Jinfeng
Tian, Yinping
Tian, Xiao
Jung, Jaesoo
Macauley, Matthew S.
Zhang, Jiabin
Wu, Peng
Wen, Liuqing
摘要： Widely distributed in nature, sulfated glycan epitopes play important roles in diverse pathophysiological processes. However, due to their structural complexity, the preparation of glycan epitopes with structurally defined sulfation patterns is challenging, which significantly hampers the detailed elucidation of their biological functions at the molecular level. Here, we introduce a strategy for site-specific chemical sulfation of glycan epitopes, leveraging enzymatic sialylation and desialylation processes to precisely control the regio-specificity of sulfation of disaccharide or trisaccharide glycan backbones. Using this method, a sulfated glycan library covering the most common sialylated glycan epitopes was prepared in high yield and efficiency. By screening a microarray prepared with this glycan library, we systematically probed their binding specificity with human Siglecs (sialic acid-binding immunoglobulin-type lectins), many of which function as glyco-immune checkpoints to suppress immune system activation. Our investigation revealed that sulfation and sialylation patterns serve as important determinants of Siglec binding affinity and specificity. Thus, these findings offer new insights for the development of research tools and potential therapeutic agents targeting glyco-immune checkpoints by modulating the Siglec signaling pathway.
分类： 药物科学 >> 药物化学 提交时间： 2024-12-30
Gao, Cheng-Long
Song, Jin-Qian
Yang, Ze-Nan
Wang, Haojie
Wu, Xin-Yuan
Shao, Changwei
Dai, Hong-Xia
Chen, Kaixian
Guo, Yue-Wei
Pang, Tao
Li, Xu-Wen
摘要： Acute lung injury is a devastating illness characterized by severe inflammation mediated by aberrant activation of macrophages, resulting in significant morbidity and mortality, highlighting the urgent need for novel pharmacological targets and drug candidates. In this study, we identified a novel target for regulating inflammation in macrophages and acute lung injury via chemical proteomics and genetics based on a marine alkaloid, naamidine J (NJ). The structures of NJ-related naamidine alkaloids were first confirmed or revised by a combination of quantum chemical calculations and X-ray diffraction analysis. NJ was found as a potential anti-inflammatory agent by screening our compound library, and CSE1L was identified by chemoproteomics as a main cellular target of NJ to inhibit inflammation in macrophages and protect against acute lung injury. Mechanistically, we demonstrated that NJ directly interacted with CSE1L on the sites of His745 and Phe903 and then inhibited the nuclear translocation and tran
分类： 药物科学 >> 遗传学 提交时间： 2024-12-26
Wang, Kun
Zhang, Yingying
Su, Zhaoming
Wang, Bei
Zhou, Yuanyang
Tong, Xiaochu
Xie, Chengying
Luo, Xiaomin
Zhang, Sulin
Zheng, Mingyue
摘要： Immune checkpoint inhibitors (ICIs) have achieved great success; however, a subset of patients exhibits no response. Consequently, there is a critical need for reliable predictive biomarkers. Our focus is on CDC42, which stimulates multiple signaling pathways promoting tumor growth. We hypothesize that an impaired function of CDC42 may serve as an indicator of a patient’s response to ICI therapy. We consider CDC42 and its downstream binding and effector proteins as a gene set, as mutations in these components could lead to defective CDC42 function. To elucidate the biomarker function of mutations within the CDC42 gene set, we curated a comprehensive discovery dataset that included seven ICI treatment cohorts. And we curated two ICI treatment validation cohorts for validation. We explored the mechanism based on The Cancer Genome Atlas database. We also examined whether combining a CDC42 inhibitor with ICI could enhance ICI’s efficacy. Mutations in the CDC42 gene set were associated with improved overall survival and progression-free survival. Furthermore, our analysis of immune response landscapes among different statuses of the CDC42 gene set supports its role as a biomarker. Animal experiments also revealed that the combination of the CDC42 inhibitor (ML141) with anti-PD-1 blockade can additively reduce tumor growth. Our study suggests that the CDC42 gene set could potentially serve as a novel biomarker for the clinical response to ICI treatment. This finding also provides insights into the potential of combining ICI and CDC42 inhibitor use for more efficient patient treatment.
分类： 药物科学 >> 药物化学 提交时间： 2024-09-20
摘要： gem-Difluoroalkenes are widely used building blocks in fluorine chemistry. Herein, a metal-free photocatalytic amination and heteroarylation method of gem-difluoroalkenes with heteroaryl carboxylic acid oxime esters as substrates is reported. This environmentally benign reaction proceeds via radical-radical cross-coupling in energy-transfer-mediated photocatalysis and can be used in the rapid construction of heteroaryl difluoroethylamine scaffolds and late-stage modification of complex pharmaceutical structures.
分类： 药物科学 >> 药物化学 提交时间： 2024-09-20
摘要： Glycan is an essential cell component that usually exists in either a free form or a glycoconjugated form. Glycosylation affects the regulatory function of glycoconjugates in health and disease development, indicating the key role of glycan in organisms. Because of the complexity and diversity of glycan structures, it is challenging to prepare structurally well-defined glycans, which hinders the investigation of biological functions at the molecular level. Chemoenzymatic synthesis is an attractive approach for preparing complex glycans, because it avoids tedious protecting group manipulations in chemical synthesis and ensures high regio- and stereo-selectivity of glucosides during glycan assembly. Herein, enzymes, such as glycosyltransferases (GTs) and glycosidases (GHs), and sugar donors involved in the chemoenzymatic synthesis of human glycans are initially discussed. Many state-of-the-art chemoenzymatic methodologies are subsequently displayed and summarized to illustrate the development of synthetic human glycans, for example, N- and O-linked glycans, human milk oligosaccharides, and glycosaminoglycans. Thus, we provide an overview of recent chemoenzymatic synthetic designs and applications for synthesizing complex human glycans, along with insights into the limitations and perspectives of the current methods.This work reviewed the recent progress in the chemoenzymatic synthesis of human glycans and provides insights into the limitations and perspectives of the current methods.
分类： 药物科学 >> 药物化学 提交时间： 2024-09-20
Zhang, Jingjing
Ren, Wenming
Liu, Xiaohui
Chen, Jingjing
Zeng, Yuteng
Xiang, Huaijiang
Hu, Youhong
Zhang, Haiyan
摘要： β-Amyloid (Aβ) aggregation is increasingly recognized as both a biomarker and an inducer of the progression of Alzheimer’s disease (AD). Here, we describe a novel fluorescent probeP14, developed based on the BODIPY structure, capable of simultaneous visualization and inhibition of Aβ aggregationin vivo.P14shows high binding affinity to Aβ aggregates and selectively labels Aβ plaques in the brain slices of APP/PS1 mice. Moreover,P14is able to visualize overloaded Aβ in both APP/PS1 and 5 × FAD transgenic micein vivo. From the aspect of potential therapeutic effects,P14administration inhibits Aβ aggregation and alleviates Aβ-induced neuronal damagein vitro, as well as reduces central Aβ deposition and ameliorates cognitive impairment in APP/PS1 transgenic micein vivo. Finally,P14is applied to monitor the progression of Aβ aggregation in the brain of 5 × FAD transgenic mice and the intervention effect itself by fluorescence imaging. In summary, the discovery of this fluorescent agent might provide important clues for the future development of theranostic drug candidates targeting Aβ aggregation in AD.
分类： 药物科学 >> 药物化学 提交时间： 2024-09-20
摘要： The development of necroptosis inhibitors has emerged as a promising strategy to effectively mitigate necroptosis-related inflammatory diseases, neurodegenerative diseases, and cancers. In this paper, we reported a series of 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole derivatives as potent necroptosis inhibitors. The representative compound 26 displayed potent anti-necroptotic activity in both human and mouse cellular assays and exhibited potent inhibitory activity against receptor-interacting protein kinase 1 (RIPK1). In vivo pharmacokinetic studies were performed to determine the oral exposure of compound 26. Finally, molecular docking elucidated that compound 26 could effectively bind to the allosteric pocket of RIPK1 and serve as a type III inhibitor. Taken together, our findings highlighted that compound 26 represented a promising lead compound for future necroptosis inhibitor development.
分类： 药物科学 >> 生物化学 提交时间： 2024-06-14
Huixu Feng
Guobin Liu
Luhan Li
Xuelian Ren
Yue Jiang
Wanting Hou
Ruilong Liu
Kun Liu
Hong Liu
He Huang
摘要： Hyperlipidemia (HLP) is a prevalent systemic metabolic disorder characterized by disrupted lipid metabolism. Statin drugs have long been the primary choice for managing lipid levels, but intolerance issues have prompted the search for alternative treatments. Matrine, a compound derived from the traditional Chinese medicine Kushen, exhibits anti-inflammatory and lipid-lowering properties. Nevertheless, the mechanism by which matrine modulates lipid metabolism remains poorly understood. Here, we investigated the molecular mechanisms underlying matrine’s regulation of lipid metabolism. Employing quantitative proteomics, we discovered that matrine increases the expression of LDL receptor (LDLR) in HepG2 and A549 cells, with subsequent experiments validating its role in enhancing LDL uptake. Notably, in hyperlipidemic hamsters, matrine effectively lowered lipid levels without affecting body weight, which highlights LDLR as a critical target for matrine’s impact on hyperlipidemia. Moreover, matrine’s potential inhibitory effects on tumor cell LDL uptake hint at broader applications in cancer research. Additionally, Thermal Proteome Profiling (TPP) analysis identified lipid metabolism-related proteins that may interact with matrine. Together, our study reveals matrine’s capacity to upregulate LDLR expression and highlights its potential in treating hyperlipidemia. These findings offer insights into matrine’s mechanism of action and open new avenues for drug research and lipid metabolism regulation.
分类： 药物科学 >> 生物化学 提交时间： 2024-06-14
Yue Jiang
Xuelian Ren
Jing Zhao
Guobin Liu
Fangfang Liu
Xinlong Guo
Ming Hao
Hong Liu
Kun Liu
He Huang
摘要： Gemcitabine (GEM) is a potent chemotherapeutic agent widely employed in the treatment of various cancers, notably pancreatic cancer. Despite its clinical success, challenges related to GEM resistance and toxicity persist. Therefore, there is a pressing need for a deeper understanding of its intracellular mechanisms and potential targets. In this study, we utilized quantitative proteomics and thermal proteome profiling (TPP) to elucidate the effects of GEM. Our proteomic analysis revealed that GEM primarily affected DNA synthesis, leading to the upregulation of cell cycle and DNA replication proteins. Additionally, enrichment analysis highlighted the activation of the p53 pathway, shedding light on GEM-induced apoptosis mechanisms. Notably, we observed the upregulation S-phase kinase-associated protein 2 (SKP2), a cell cycle and chemoresistance regulator, in response to GEM treatment. Combining SKP2 inhibition with GEM showed synergistic effects in both cellular and animal models, suggesting SKP2 as a potential target for enhancing GEM sensitivity and overcoming chemoresistance. Furthermore, through TPP, we explored potential binding targets of GEM, which implies GEM’s broad anticancer effects. Together, these findings provide valuable insights into GEM’s molecular mechanisms and offer potential targets for improving treatment efficacy. This research holds the promise of advancing personalized treatment strategies and opening avenues for novel combination therapies to enhance outcomes in pancreatic cancer.
分类： 药物科学 >> 药物设计 提交时间： 2024-05-13
Yulong Shi
Chongwu Li
Xinben Zhang
Cheng Peng
Peng Sun
Qian Zhang
Leilei Wu
Ying Ding
Dong Xie
Zhijian Xu
Weiliang Zhu
摘要： As key oncogenic drivers in non-small-cell lung cancer (NSCLC), various mutations in the epidermal growth factor receptor (EGFR) with variable drug sensitivities have been a major obstacle for precision medicine. To achieve clinical-level drug recommendations, a platform for clinical patient case retrieval and reliable drug sensitivity prediction is highly expected. Therefore, we built a database, D3EGFRdb, with the clinicopathologic characteristics and drug responses of 1,339 patients with EGFR mutations via literature mining. On the basis of D3EGFRdb, we developed a deep learning-based prediction model, D3EGFRAI, for drug sensitivity prediction of new EGFR mutation-driven NSCLC. Model validations of D3EGFRAI showed a prediction accuracy of 0.81 and 0.85 for patients from D3EGFRdb and our hospitals, respectively. Furthermore, mutation scanning of the crucial residues inside drug-binding pockets, which may occur in the future, was performed to explore their drug sensitivity changes. D3EGFR is the first platform to achieve clinical-level drug response prediction of all approved small molecule drugs for EGFR mutation-driven lung cancer and is freely accessible at https://www.d3pharma.com/D3EGFR/index.php.
分类： 药物科学 >> 其他 分类： 医学、药学 >> 药学 提交时间： 2024-05-10
Yingquan WEN
Ziyuan ZOU
Guanguan ZHAO
Mengjiao ZHANG
Yongxin ZHANG
Gaihong WANG
Jingjing SHI
Yuanyang WANG
Yeyu SONG
Huixia WANG
Ruyue CHEN
Dongxuan ZHENG
Xiaoqun DUAN
Yameng LIU
Frank J GONZALEZ
Jian-Gao FAN
Cen XIE
摘要： The progression of simple steatosis to non-alcoholic steatohepatitis (NASH) has emerged as a significant health concern. The activation of FXR shows promise in countering this transition and its detrimental consequences. However, the specific alterations within the NASH-related transcriptional network remain elusive, hindering the development of more precise and effective therapeutic strategies. Through a comprehensive analysis of liver RNA-seq data from human and mouse NASH samples, we identified central perturbations within the NASH-associated transcriptional network, including disrupted cellular metabolism and mitochondrial function, decreased tissue repair capability, and increased inflammation and fibrosis, thus shedding light on the complex molecular mechanisms underlying NASH progression. By employing integrated transcriptome profiling of diverse FXR agonists-treated mice, FXR liver-specific knockout mice, and publicly available human datasets, we determined that hepatic FXR activation effectively ameliorated NASH by reversing the dysregulated metabolic and inflammatory networks implicated in NASH pathogenesis. This mitigation encompassed resolving fibrosis, reducing immune infiltration, and creating an immune microenvironment that mirrors the positive trends observed in clinical disease progression. By understanding the core regulatory network of FXR, which is directly correlated with disease severity and treatment response, we identified approximately one-third of the patients who could potentially benefit from FXR agonist therapy. A similar analysis involving intestinal RNA-seq data from FXR agonists-treated mice and FXR intestine-specific knockout mice revealed that intestinal FXR activation attenuates intestinal inflammation, and has promise in attenuating hepatic inflammation and fibrosis. Collectively, our study uncovers the intricate pathophysiological features of NASH at a transcriptional level and highlights the complex interplay between FXR activation and both NASH progression and regression. These findings contribute to precise drug development, utilization, and efficacy evaluation, ultimately aiming to improve patient outcomes.
分类： 药物科学 >> 结构生物学 提交时间： 2024-04-27
Heng Zhang
Yuling Yin
Tianwei Zhang
Canrong Wu
Wen Hu
Xinheng He
Benxun Pan
Sanshan Jin
Qingning Yuan
H. Eric Xu
Yi Jiang
摘要： The norepinephrine transporter (NET) plays a pivotal role in regulating neurotransmitter balance and is critical for normal physiology and neurobiology. Dysfunction of NET has been implicated in numerous neuropsychiatric diseases including depression, anxiety, attention deficit hyperactivity disorder, and Parkinson’s disease. Here we report cryo-EM structures of NET in apo and substrate-bound forms, as well as complexes with six antidepressants. The structures reveal an unexpected NET dimer interface predominantly mediated by cholesterol and lipid molecules. The substrate norepinephrine is found to bind deep within the central binding pocket, with its amine group interacting with a conserved aspartate. The structures also provide insight into antidepressant recognition, including how subtle differences in binding poses confer selectivity over other monoamine transporters. Together these breakthrough findings significantly advance our understanding of NET regulation and inhibition, providing templates for designing improved antidepressants to treat neuropsychiatric disorders.
分类： 药物科学 >> 结构生物学 提交时间： 2024-04-17
摘要： The adenosine A3 receptor (A3AR) belongs to a subfamily of G protein-coupled receptors and is an important therapeutic target for conditions including inflammation and cancer. The clinical compounds CF101 and CF102 are potent and selective A3AR agonists, but the structural basis of their recognition was unknown. Here we present the cryogenic electron microscopy structures of the full-length human A3AR bound to CF101 and CF102 at 3.3-3.2 Å resolution in complex with heterotrimeric Gi protein. These agonists bind within the orthosteric pocket, with their adenine components engaging in conserved interactions while their substituted 3-iodobenzyl groups exhibit different orientations. Swapping extracellular loop 3 (ECL3) of A3AR onto other adenosine receptor subtypes enabled CF101/CF102 binding and receptor activaton, and mutations in key residues, including His3.37, Ser5.42 and Ser6.52 that form a unique subpocket in A3AR, abolished receptor activation, highlighting these structural elements are critical for ligand selectivity. Compared to inactive A2AAR, the A3AR structures reveal conserved mechanism of receptor activation, including an outward shift of TM6. These structures provide key insights into molecular recognition and signaling mechanisms of A3AR, which should aid rational design of subtype-selective ligands targeting this important class of adenosine receptors.
分类： 药物科学 >> 药物设计 提交时间： 2024-04-10
摘要： Halogen bonds (XBs) are essential non-covalent interactions in molecular recognition and drug design. Current studies on XBs in drug design mainly focus on the interactions between halogenated ligands and target proteins, lacking a systematic study on naturally existing and artificially prepared halogenated residue XBs (hr_XBs) and their characteristics. Here, we conducted a computational study on the potential hr_XBs in proteins/peptides using database searching, quantum mechanics calculations, and molecular dynamics simulations. XBs at protein-peptide interaction interfaces are found to enhance their binding affinity. Additionally, the formation of intramolecular XBs (intra_XBs) within proteins may significantly contribute to the structural stability of structurally flexible proteins, while having a minor impact on proteins with inherently high structural rigidity. Impressively, introducing halogens without the formation of intra_XBs may lead to a decrease in protein structural stability. This study enriches our comprehension of the roles and effects of halogenated residue XBs in biological systems.
分类： 药物科学 >> 结构生物学 提交时间： 2024-02-29
摘要： Succinic acid, a tricarboxylic acid (TCA) cycle intermediate, significantly influences mitochondrial reactive oxygen species homeostasis through the G protein-coupled succinate receptor (SUCR1, also called GPR91), linking it to various physiological and pathological processes. Despite SUCR1’s pivotal role in mediating effects leading to liver fibrosis, hypertension, angiogenesis, inflammation, and offering a therapeutic target for multiple diseases, its activation mechanism by diverse ligands and interaction with downwards G protein remains poorly understood. This study presents the cryo-electron microscopy (cryo-EM) structures of SUCR1 in complex with inhibitory G protein (Gi) bound to succinic acid, maleic acid, and compound 31, a high-affinity agonist. These structures elucidate the distinct ligand binding modes, uncover the activation signal cascade, and detail the G protein coupling mechanism of SUCR1. Our findings provide a comprehensive structural basis for SUCR1 activation, paving the way for structure-based drug design aimed at SUCR1-related pathologies.
分类： 药物科学 >> 结构生物学 提交时间： 2024-02-24
Heng Liu
Shimeng Guo
Antao Dai
Peiyu Xu
Xin Li
Sijie Huang
Xinheng He
Kai Wu
Xinyue Zhang
Dehua Yang
Xin Xie
H. Eric Xu
摘要： The orphan receptor GPR30, previously classified as a G protein-coupled estrogen receptor (GPER), has been a subject of debate regarding its ligand specificity. Through an integrative approach combining structure elucidation, biochemical binding, and cell signaling assays, we demonstrate that estrogen does not directly bind to or activate GPR30. Cryo-EM structures of GPR30 reveal an unexpected hydrophilic ligand-binding pocket, with striking differences from classical hydrophobic steroid-binding sites, inconsistent with estrogen binding. We further confirmed hydrophilic agonists like Lys05 as true activators of GPR30, providing structural insights into their binding mechanism and receptor activation. Our findings necessitate a paradigm shift in defining GPR30’s role in estrogen signaling, indicating that its activation occurs through mechanisms independent of estrogen binding. This study opens new avenues for developing targeted GPR30 ligands and reinterpreting its role in estrogen-mediated processes.
分类： 药物科学 >> 结构生物学 提交时间： 2024-02-21
摘要： Bombesin receptor subtype-3 (BRS3) is an important orphan G protein-coupled receptor that regulates energy homeostasis and insulin secretion. As a member of the bombesin receptor (BnR) family, which includes neuromedin B receptor (NMBR) and gastrin-releasing peptide receptor (GRPR), the lack of known endogenous ligands and high-resolution structure has impeded understanding of BRS3 signaling and function. Here, we present cryogenic electron microscopy (cryo-EM) structures of BRS3 in complex with heterotrimeric Gq protein in three states: apo, bound to the pan-BnR agonist, BA1, and bound to the synthetic BRS3-specific agonist MK-5046. These structures reveal the architecture of the orthosteric ligand pocket underpinning molecular recognition. Comparisons with BnR members provide insights into the structural basis for BRS3’s selectivity and low affinity for bombesin peptides. Examination of conserved micro-switches suggests a shared activation mechanism among BnRs. Together our results enable deeper exploration of BRS3’s ligand selectivity, signaling, and therapeutic targeting for diabetes and obesity.
分类： 药物科学 >> 药物设计 提交时间： 2024-02-20
Jin Liu
Yike Gui
Jingxin Rao
Jingjing Sun
Gang Wang
Qun Ren
Ning Qu
Buying Niu
Zhiyi Chen
Xia Sheng
Yitian Wang
Mingyue Zheng
Xutong Li
摘要： Ensuring drug safety in the early stages of drug development is crucial to avoid costly failures in subsequent phases. However, the economic burden associated with detecting drug off-targets and potential side effects through in vitro safety screening and animal testing is substantial. Drug off-target interactions, along with the adverse drug reactions they induce, are significant factors affecting drug safety. To assess the liability of candidate drugs, we developed an artificial intelligence model for the precise prediction of compound off-target interactions, leveraging multi-task graph neural networks. The outcomes of off-target predictions can serve as representations for compounds, enabling the differentiation of drugs under various ATC codes and the classification of compound toxicity. Furthermore, the predicted off-target profiles are employed in ADR enrichment analysis, facilitating the inference of potential ADRs for a drug. Using the withdrawn drug Pergolide as an example, we elucidate the mechanisms underlying ADRs at the target level, contributing to the exploration of the potential clinical relevance of newly predicted off-target interactions. Overall, our work facilitates the early assessment of compound safety/toxicity based on off-target identification, deduces potential ADRs of drugs, and ultimately promotes the secure development of drugs.
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