分类: 药物科学 >> 药物设计 提交时间: 2024-05-13
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
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
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
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
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: 2024-02-07
摘要: A new cembranolide, namely, sinupendunculide A (1), along with eight known related compounds (29), was isolated from the South China Sea Soft coral Sinularia pendunculata. The structure of sinupendunculide A (1) was established by extensive spectroscopic analysis and X-ray diffraction experiments. In a bioassay, anti-colorectal cancer (CRC) activity was performed, and the results showed that several compounds exhibited cytotoxicity against RKO cells, and a preliminary structure-activity relationship was analysed. Meanwhile, the most effective compound 7 was proven to increase reactive oxygen species levels, which promoted cell apoptosis and inhibited cell proliferation.
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 >> 药物设计 提交时间: 2024-02-06
摘要: Continuous exploration of the chemical space of molecules to find ligands with high affinity and specificity for specific targets is an important topic in drug discovery. A focus on cyclic compounds, particularly natural compounds with diverse scaffolds, provides important insights into novel molecular structures for drug design. However, the complexity of their ring structures has hindered the applicability of widely accepted methods and software for the systematic identification and classification of cyclic compounds. Herein, we successfully developed a new method, D3Rings, to identify acyclic, monocyclic, spiro ring, fused and bridged ring, and cage ring compounds as well as macrocyclic compounds. By using D3Rings, we completed the statistics of cyclic compounds in 3 different databases, e.g., ChEMBL, DrugBank, and COCONUT. The results demonstrated the richness of ring structures in natural products, especially spiro, macrocycles, fused and bridged rings. Based on this, three deep generative models, namely VAE, AAE, and CharRNN, were trained and used to construct two datasets similar to DrugBank and COCONUT but 10 times larger than them. The enlarged datasets were then used to explore the molecular chemical space, focusing on complex ring structures, for novel drug discovery and development. Docking experiments with the newly generated COCONUT-like dataset against three SARS-CoV-2 target proteins revealed that an expanded compound database improves molecular docking results. Cyclic structures were exhibited the best docking scores among the top-ranked docking molecules. These results suggest the importance of exploring the chemical space of structurally novel cyclic compounds and continuous expansion of the library of drug-like compounds to facilitate the discovery of potent ligands with high binding affinity to specific targets. D3Rings is now freely available at http://www.d3pharma.com/D3Rings/.