BIOORGANIC & MEDICINAL CHEMISTRY
·
2023
·
IF 3.5
Lu Liu,Zhendong Song,Guangjin Fan,Linlin Lou,Yuanxiang Wang,Xiaolei Zhang,Xiao-Feng Xiong
KRAS serves as a vital regulator for cellular signaling and drives tumor pathogenesis after mutation. Despite extensive research efforts spanning several decades, targeting KRAS is still challenging due to the multiple KRAS mutations and the emergence of drug resistance. Interfering the interactions between KRAS and SOS1 is one of the promising approaches for modulating KRAS functions. Herein, we discovered small-molecule SOS1 agonists with novel indazole scaffold. Through structure-based optimization, compound 11 was identified with high SOS1 activation potency (p-ERK EC 50 = 1.53 μM). In HeLa cells, compound 11 enhances cellular RAS-GTP levels and exhibits biphasic modulation of ERK1/2 phosphorylation through an on-target mechanism and presents the therapeutic potential to modulate RAS signaling by activating SOS1.
研究领域:
肿瘤学
·
分子生物学
·
药物化学
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DOI
PubMed
高影响因子
BIOORGANIC & MEDICINAL CHEMISTRY
·
2024
·
IF 3.3
Xue Guo,Zhijie Luo,Ying Qi,Xiaoyuan Hei,Xin Zhang,Xuli Cao,Mingcheng Qian,Shuai Zhao,Yanan Hou,Xin Chen
19 derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides ( H 1 - H 19 ) and 5 derivatives of 1-benzyl-5-arylpyrazole-3-carboxamides ( J 1 - J 5 ) have been designed and synthesized as potential negative allosteric modulators (NAMs) for the β 2 -adrenergic receptor (β 2 AR). The new pyrazole derivatives were screened on the classic G-protein dependent signaling pathway at β 2 AR. The majority of 1-benzyl-3-aryl-pyrazole-5-carboxamide derivatives show more potent allosteric antagonistic activity against β 2 AR than Cmpd-15, the first reported β 2 AR NAM. However, the 1-benzyl-5-arylpyrazole-3-carboxamide derivatives exhibit very poor or even no allosteric antagonistic activity for β 2 AR. Furthermore, the active pyrazole derivatives have relative better drug-like profiles than Cmpd-15. Taken together, we discovered a series of derivatives of 1-benzyl-3-arylpyrazole-5-carboxamides as a novel scaffold of β 2 AR NAM.
研究领域:
药理学
·
分子生物学
·
药物化学
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DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Yazhou Wang,Hai Wang,Qingqing Li,Ying Zhang,Rupeng Dai,Jun Wu,Yanan Zhang,Xiaomeng Zhang,Liwen Zhao,Jian Liu
Nonalcoholic steatohepatitis (NASH) has become a leading cause of liver fibrosis and hepatocellular carcinoma; however, there are no efficient drugs for NASH therapy. Acetyl-CoA carboxylase (ACC) is a crucial enzyme regulating lipid metabolism that is considered as a potential target for NASH treatment. Allosteric inhibitors target nonfunctional sites, which tend to be highly variable in protein families; thus, allosteric inhibitors are explored as an important source of drug candidates. Herein, several hotspot residues are initially identified by utilizing molecular dynamic simulation, MM-GBSA calculation, and alanine mutation. Then, focusing on the interaction with hotspot residues, several cyclobutane-based ACC allosteric inhibitors are designed, synthesized, and biologically evaluated. Among them, B1 demonstrates potent ACC inhibitory activity in vitro, a higher distribution in liver than in other tissues, and a potent therapeutic effect for NASH in vivo, making it a promising candidate for the treatment of NASH.
研究领域:
药理学
·
分子生物学
·
医学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2025
·
IF 13.2
Jingui Ma,Zhigang Yang,Hui Yuan,Xinmin He,Mei Wang,Weibiao Wang,Lingling Yang,Fen Ma,Weiman Zhang,Gidion Wilson,Yuping Sa,Guoning Chen,Xueqin Ma
Hyaluronidase (HAase) degrades hyaluronic acid (HA), a key glycosaminoglycan of the extracellular matrix involved in tissue hydration, cell motility, and inflammation. Excessive HAase activity is associated with diseases, including cancer metastasis and inflammation, making HAase inhibitors vital for treatment strategies. Meanwhile, efficiently analyzing active ingredients in complex herbal medicines is key for drug discovery, but developing a simple and accurate method remains challenging. Here, an integrated approach combining paper-based sensing and column-free affinity chromatography to efficiently screen potential HAase inhibitors from herbal sources was established. The paper-based sensing module uses HA's rheological properties to quickly assess the inhibitory effects of herbal extracts on HAase. Herbals with inhibitory activity are then analyzed using affinity chromatography to capture, separate, and identify bioactive components interacting with HAase. The feasibility of both biosensing and affinity chromatography was validated using negative and positive control drugs, and Galla chinensis was successfully identified from 40 herbal samples as a potent HAase inhibitor, with tannic acid (TA) being the active compound (IC 50 = 51.22 μM). Molecular docking and dynamics simulations revealed a strong binding affinity between TA and HAase. TA's anti-inflammatory effects were further confirmed by its significant inhibition of LPS-induced IL-4, IL-5, IL-6, and TNF-α in cell experiments. In summary, this integrated strategy presents a promising and efficient approach for the discovery and development of novel HAase inhibitors, as well as other enzyme inhibitors derived from natural medicinal sources.
研究领域:
药物化学
·
分析化学
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天然产物研究
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酶学
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药物研发
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产品关联
DOI
高影响因子
JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2025
·
IF 6.2
Wuyang Hua,Yu Cheng,Fenglin Li,Yanhui Li,Zhongkui Lu,Li Li,Dan Wang,Jingxue Liu
Hepatocellular carcinoma remains a fatal disease with a high metastasis risk. Matrix metalloproteinases (MMPs) are key mediators of metastasis and are potential therapeutic targets. Using a natural product derivatization strategy, we designed novel anticancer agents based on resveratrol─a dietary polyphenol found in grapes and other food sources with known MMP-suppressive effects. Although the resveratrol derivative amino-Res (5) showed promising in vitro activity, its poor metabolic stability limited its in vivo efficacy. To address this, we synthesized 14 urea-containing derivatives of amino-Res. Among them, compound 6k exhibited improved metabolic stability and potent anticancer activity both in vitro and in vivo. Mechanism studies revealed that 6k arrests the cell cycle in the G2/M phase, induces intrinsic apoptosis, and inhibits migration and invasion through MMP suppression. This work demonstrates the value of derivatizing dietary natural products for developing novel anticancer agents.
研究领域:
药物化学
·
肿瘤学
·
药理学
·
药物研发
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DOI
PubMed
高影响因子
SEPARATION AND PURIFICATION TECHNOLOGY
·
2025
·
IF 9
Wenxin Wang,Huanxin Xu,Fanghong Ning,Junfen Wan
Ascomycin plays an important role in the treatment of various autoimmune diseases and skin diseases; its application prospects in the pharmaceutical market are promising. As an intermediate of pimecrolimus, separating and purifying high-purity ascomycin is a key step in producing high-quality medicines. Moreover, ascomycin and its key impurities have similar structures, which makes the separation and purification process very challenging. Therefore, this study developed a new separation and purification system that combines the synergistic effects of reversed-phase polymer resin and macroporous adsorption resin to provide a novel separation and preparation process. In the static adsorption stage, HZ-816 was chosen as the optimal resin, and used Lagergren's second-order kinetic and the Temkin isotherm model as the best adsorption models; the adsorption process was spontaneous, exothermic, and multi-layer adsorption. To achieve optimal purification, we used 0.5 mg/mL ascomycin, a 4 BV/h flow rate, and a sample volume of 110 BV. The eluent was 70 % ethanol, with a flow rate of 2 BV/h. The obtained purity was 82.07 %, and the recovery rate was 62.68 %. During the reversed-phase polymer chromatography stage, by optimizing parameters such as the elution flow rate and loading quantity, the purity was increased to 98.55 %, with a recovery rate of 85.87 % and an elution rate of 95.54 %. The yield was 53.82 %. Through the optimization of experimental procedures and material selection, this study has laid a solid performance foundation for subsequent cost-effective, highly efficient, and sustainable applications, providing a reference for the technological advancement of the ascomycin separation and purification industry.
研究领域:
药物化学
·
分离科学
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色谱技术
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生物过程工程
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药物研发
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产品关联
DOI
高影响因子
BIOORGANIC CHEMISTRY
·
2025
·
IF 4.7
Linxuan Li,Ruifeng Wang,Jianzhong Zhu,Fangqi Cao,Jingli Min,Defang Ouyang,Ligen Lin
Nicotinamide adenine dinucleotide (NAD + ) is a crucial cofactor for maintaining cellular homeostasis, and its level is strictly regulated by the rate-limiting enzyme nicotinamide phosphoribosyltransferase (NAMPT). Small molecule NAMPT agonists hold great potential to boost NAD + level, while only few agonists were available currently. Herein, we established a rapid screening workflow for NAMPT agonists by integrating molecular docking and molecular dynamics simulations. In brief, the high-throughput docking was firstly performed on 1.3 million compounds from the ZINC20 Lead-like subset, and the top 20 candidates were further evaluated by all-atom molecular dynamics simulations and MM/GBSA assessments, ultimately identifying three potential candidates. Among them, 3,4-dihydro-1H-isoquinolin-2-yl-[4-(2H-tetrazol-5-yl)phenyl]methanone (DIPM) enhanced NAMPT enzymatic activity by approximately threefold at the concentration of 20 μM, with the EC 50 value of 3.366 μM and a maximum effect approximate 1.05-fold that of NAT. DIPM binds stably to NAMPT with a binding free energy of −30.86 kcal/mol. Its binding sites are located far from the catalytic active center of NAMPT and do not interfere with the substrate channel, indicating that DIPM activates NAMPT through an allosteric mechanism. DIPM (20 μM) elevated intracellular NAD + levels by approximately twofold with no obvious toxicity in C2C12 myotubes. In a dexamethasone-induced C2C12 myotube atrophy model, DIPM (20 μM) restored myotube diameter, decreased the expression of atrophy markers Atrogin-1 and muscle ring finger 1 (MuRF1), and increased myosin heavy chain (MyHC) expression. As a potent, low-toxic, non-competitive allosteric NAMPT agonist, DIPM represents a promising lead compound for treating conditions involving muscle wasting.
研究领域:
生物化学
·
分子生物学
·
药理学
·
计算化学
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药物研发
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产品关联
DOI
PubMed
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2025
·
IF 4
Yong Li,Ying Ding,Chenxu Liu,Yunchao Li,Xinyu Guo,Meidan Huo,Linjing Jia,Haiwei Xu,Hailing Qiao,Na Gao
Cytochrome P450 2E1 (CYP2E1) plays an important role in inflammatory disease, but the role of CYP2E1 in gout remains elusive. The pharmacokinetics in rats of Q11, a CYP2E1 inhibitor synthesized by our group, were measured. The anti-inflammatory and uric acid (UA)-lowering levels mechanism of Q11 was investigated in hyperuricemic (HUA) mice and acute gouty arthritis (AGA) rats, and in macrophage cells stimulated by monosodium urate (MSU). The half-life (t 1/2 ) of Q11 in the ankle joint and kidney was approximately 9 h, which was more than 4 times longer than that in plasma. The expression of CYP2E1 was increased in the kidneys of HUA mice and in the ankles of AGA rats. Q11 reduced plasma UA levels in HUA mice by decreasing xanthine oxidase (XOD) activity. In addition, Q11 also decreased renal inflammatory injury in HUA mice. Moreover, Q11 decreased the levels of IL-1β and TNF-α in AGA rats, increased the levels of catalase (CAT) and glutathione (GSH), and blocked the activation of the NLRP3 inflammasome. A similar phenomenon was observed in J774A.1 and THP-1 cells treated with sodium urate.CYP2E1 may be a new therapeutic target for the treatment of gout and Q11 has the dual effect of being anti-inflammatory and lowering UA. Significance Statement The specific cytochrome P450 2E1 (CYP2E1) inhibitor Q11 reduced plasma uric acid (UA) levels by decreasing xanthine oxidase (XOD) activity in a gout animal model, while attenuating joint and renal inflammatory injury through the inhibition of oxidative stress and NLRP3 inflammasome activation.
研究领域:
药理学
·
炎症
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风湿病学
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代谢性疾病
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药物研发
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Dongqing Ding,Mengyun Chen,Wei Li,Zhousong Luo,Yongpei Xu,Wenhui Zong,Wenzhong Li,Jian Chen
Wilson's disease is a type of neurogenetic disease associated with a disorder of copper metabolism. In general, de‑coppering drugs such as copper chelators and zinc preparations are used to treat this condition. However, the effects of zinc preparations are slow, and long-term use of copper chelators results in some adverse reactions (e.g., nephrotoxicity). In this study, we developed a novel modified microcrystalline cellulose-based adsorbent (MCC-NS) as a gastrointestinal-restricted sequestrant to remove excess copper from the body. Scanning electron microscopy and X-ray photoelectron spectroscopy were performed to characterize the resulting adsorbent (also called de‑coppering cellulose). These methods revealed the successful immobilization of amino and sulfhydryl groups on the surface of MCC. In addition, de‑coppering performance tests revealed the high copper affinity of MCC-NS. This adsorbent removes excess serum copper in a timely manner in Cu-overdosed mice and can reduce copper deposition in tx-j mice, thereby alleviating liver damage. In vivo biosafety evaluation experiments revealed that long-term MCC-NS administration did not injure the primary organs of the mice. Collectively, our findings suggest the potential of as-prepared de‑coppering cellulose as an oral gastrointestinal-restricted copper sequestrant for treating Wilson's disease with few adverse reactions.
研究领域:
药物化学
·
胃肠病学
·
遗传性疾病
·
生物材料
·
药物研发
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2025
·
IF 4.7
Zhiling Chen,Jie Song,Mingyue Zhang,Jie Ding,Can Wang,Zihan Xu,Pinming Liu,Tao Zhuang,Guisen Zhang
Palbociclib (PAL) is a selective cyclin-dependent kinase 4/6 inhibitor and widely used in the clinical management of advanced breast cancer. However, its clinical utility is restricted by poor bioavailability, stemming from its negligible aqueous solubility, and dose-limiting adverse effects. Drug-drug salts are intensively investigated to tailor physicochemical properties of drug candidates and achieve synergistic effects. Non-steroidal anti-inflammatory drugs (NSAIDs) have garnered increasing attention for their antitumor potential in recent years. In this study, three novel drug-drug salts of PAL with diclofenac (DIC), aceclofenac (ACE), and naproxen (NAP) were synthesized via evaporative crystallization. Single-crystal and powder X-ray diffraction, thermal analysis, infrared spectroscopy, and Hirshfeld surface analysis were employed to confirm their molecular structures. Equilibrium solubility studies revealed a 1.5 to 2.8-fold solubility enhancement for PAL-NSAIDs salts at pH 7.4 buffer. Accelerated stability studies demonstrated excellent physical stability of the PAL-NSAIDs salts for 2 months. In vitro cytotoxicity assays against bladder cancer J82 cell lines demonstrated significantly improved antitumor activity for PAL-DIC, PAL-ACE, and PAL-NAP, with 2.1-fold, 1.6-fold, and 4.9-fold improvement over PAL alone, respectively. Moreover, the oral bioavailability of PAL in PAL-NAP was improved 2.5 times in rats when compared to the single PAL. This study proposed a robust strategy to enhance PAL’s solubility and anticancer efficacy by designing drug-drug salts.
研究领域:
药学
·
肿瘤学
·
药物研发
·
晶体工程
·
药代动力学
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产品关联
DOI
高影响因子
CRYSTAL GROWTH & DESIGN
·
2025
·
IF 3.4
Mukhammet N. Gabdulkhaev,Nailya F. Idiyatullina,Khasan R. Khayarov,Artem O. Surov,Marat A. Ziganshin,Valery V. Gorbatchuk
Olanzapine is among the drugs with notoriously elusive polymorphs that are challenging to prepare in their phase-pure form. A first solution to this problem is offered in the present work using the ability of water to compete with organic solvent for inclusion in the drug crystal lattice and the ability of solvate-hydrates with an optimal composition to give a solvent-free amorphous olanzapine and its phase-pure polymorph II upon desolvation. In the screening performed, saturation of the drug solid forms with solvent vapors was used to select an organic solvent that could be partially or completely replaced by vapors of water in the solvate. Besides, water vapors were found to be passive enough in comparison with vapors of other studied solvents in their ability to change the polymorphic state of olanzapine or be included by its stable form. The conditions used for preparation of the amorphous olanzapine form are mild enough to prevent its partial thermal decomposition. These conditions also create phase restrictions that stop the desolvation of solvate-hydrate on the intermediate Ostwald stage of polymorph II that is phase-pure above the sensitivity level of powder X-ray diffractometry and thermal analysis.
研究领域:
药物晶体学
·
固态化学
·
多晶现象
·
药物研发
✓ 已验证
产品关联
DOI
高影响因子
DRUG METABOLISM AND DISPOSITION
·
2025
·Vol. 53
·期 8
·100127
·
IF 4
Dehu Dou,Jing Lu,Ali Fan,Xijing Chen
DTX-007 is a double-stranded small-interfering RNA that decreases the expression of the proprotein convertase subtilisin/kexin type 9 protein through downregulation of its mRNA by conjugating with 3 N-acetylgalactosamine moieties to improve its hepatic distribution when administered via subcutaneous injection for the treatment of hypercholesterolemia. The nonclinical pharmacokinetics and the absorption, distribution, metabolism, and excretion characteristics of DTX-007 were evaluated in both in vivo and in vitro systems. Plasma protein binding exhibited concentration dependence across all examined species, approximating 99% at clinically relevant concentrations in humans. DTX-007 was absorbed after subcutaneous injection, with a mean half-life of around 0.9 hours in rats and 7.4 hours in monkeys following a dosage of 3 mg/kg. Our analysis indicates that the plasma pharmacokinetics for area under the concentration–time curve and C max of DTX-007 are approximately dose proportional and confirmed a linear relationship indicating approximately linear pharmacokinetics. DTX-007 is primarily transported to the liver by asialoglycoprotein receptor-mediated absorption, with a significantly prolonged half-life (t 1/2 ) of 87.5 hours in the liver. The tissue to plasma concentration ratio of DTX-007-AS was greatest in the liver (4589) and kidney (536). DTX-007 was metabolized by nucleases rather than cytochrome P450 isozymes across many species, with no metabolites peculiar to humans. The primary metabolites in human and monkey were AS-3'N-1 (0.19%) and AS-5'N-2 (0.96%), respectively. Renal and fecal excretion constituted minor pathways for the removal of DTX-007. In the 1 mg/kg dosage group, proprotein convertase subtilisin/kexin type 9 protein levels were slightly diminished by 15 days postadministration (63%). Subcutaneous injections of cynomolgus monkeys at doses of 1, 3, and 10 mg/kg led to a substantial decrease in serum low-density lipoprotein cholesterol levels (28%–59%). It demonstrated similar pharmacokinetics profile in both species, indicating significant higher bioavailability than the approved small-interfering RNA drug and long-term effect on pharmacodynamic markers. Significance Statement This study describes the ADME of GalNAc-RNA drug in rats and monkeys in vivo and across human and animal matrices in vitro. These studies disclose the excellent ADME profile with higher bioavailability than the approved siRNA drug and support the interpretation of toxicology studies, helping characterize the disposition of drug in humans and support the clinical use. It also highlights adequate exposure of drug to the target organ liver and long-term effect on pharmacodynamic markers after single dose.
研究领域:
药理学
·
药物研发
·
分子治疗学
·
RNA干扰
·
生物药剂学
·
毒理学
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）