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： 物理学 >> 核物理学 提交时间： 2023-06-18 合作期刊: 《Nuclear Science and Techniques》
摘要： The N-terminal domain of heat shock protein 90 (Hsp90N) is responsible for the catalytic activity of Hsp90. The reported inhibitors of Hsp90 bind to this domain and would inhibit tumor growth and progression. Here, we synthesized FS23, a small molecule inhibitor of hsp90 and collected X-ray diffraction data of the complex crystal of Hsp90-FS23. High resolution X-ray crystallography shows that FS23 interacted with Hsp90N at the nucleotide binding cleft, and this suggests that FS23 may complete with nucleotides to bind to Hsp90N. The crystal structure and the interaction between Hsp90N and FS23 suggest a rational basis for the design of novel antitumor drugs.
分类： 药物科学 >> 药物化学 提交时间： 2024-02-07
摘要： Two new cladiellin-type diterpenoids (1 and 2), and four known related compounds 3-6, were isolated from the South China Sea soft coral Cladiella krempfi. Compound 2 is the third example of cladiellins of an unusual peroxy group at C-6 position in C. krempfi. The structures and absolute configurations of the new compounds were established by extensive spectroscopic analysis, X-ray diffraction, and/or chemical correlation. In bioassay, all the compounds were evaluated for the cytotoxicity and the EGFR inhibitory activity. Molecular docking experiment was conducted to study the structure-activity relationship of cladiellin-type diterpenoids on EGFR inhibitory activity.
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： 2024-02-20
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.
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 >> 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 >> 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 >> 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 >> 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.
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