CHEMISTRY & BIODIVERSITY
·
2024
·
IF 2.3
Xue-Song Tang,Lin-Yu He,Sheng-Nan Li,Wen-Cheng Zhang,Ze-Yu Wu,Ai-Ling Hui
Vascular dementia (VaD) is a neurodegenerative disease resulting from cerebral vascular obstruction, leading to cognitive impairment, and currently lacks effective treatment options. Due to its complex pathogenesis, multi-target drug design (MTDLs) strategies are considered among the most promising therapeutic approaches. In this study, we designed and synthesized a series of novel indanone derivatives targeting targets related to vascular health and dementia. The results indicated that compound C 5 exhibited excellent acetylcholinesterase inhibitory activity (IC 50 =1.16 0.41 μM) and anti-platelet aggregation activity (IC 50 =4.92±0.10 μM) within ranges of 0.1–1000 μM and 0.03–300 μM, respectively, possibly mediated by molecular docking interactions. Furthermore, compound C 5 demonstrated protective effects on cells at concentrations ≤50 μM, significantly reducing the release of nitric oxide (NO), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) in a concentration-dependent manner, showcasing its potent neuroinflammatory inhibitory effects. Anti-inflammatory therapies are regarded as effective strategies for treating VaD. Therefore, compound C 5 holds promise as a novel candidate drug for further investigation into the treatment of vascular dementia. Graphical
研究领域:
神经病学
·
药理学
·
药物设计
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CHEMICAL RESEARCH
·
2022
·
IF 1.097
Tiandi Ding,HaiJiao Chen,Yan Li,Ying Li,Ying Zhi,Zhiqiang Qu,Qiang Sun,Qingqiang Yao,Bo Liu
Sphingosine kinase is a lipid kinase that catalyzes the phosphorylation of sphingosine to sphingosine-1-phosphate. Sphingosine-1-phosphate is a bioactive lipid that regulates biological processes. The overexpression of sphingosine kinases is related to a variety of pathophysiological conditions. For example, SphK1 has been shown to be highly expressed in various cancer cells including ovarian, cervical, colon, stomach, lung, and brain cancer. Inhibition of sphingosine kinases is a promising way to treat diseases such as cancer. Through computer-aided drug design, we have discovered a new SphK1 inhibitor named Amb30572637 (SAMS10). In this report, we describe the discovery process and biological characteristics. In biochemical experiments, SAMS10 shows a prominent inhibitory effect on SphK1, with an IC50 value of 9.8 μM. Subsequent MTT experiments show that SAMS10 has anticancer effects toward A549, SKVO3, A375, and LOVO cell lines and has essentially no cytotoxicity against the healthy cell L929. SAMS10 has significant inhibitory activity against the A549 and LOVO cell lines, with IC50 values of 14.64 and 14.48 μM, respectively. It belongs to a moderately active SphK1 inhibitor with lower anticancer activity than the control compound cisplatin, but the effect of SAMS10 toward SphK1 and its anticancer activity indicate that it is a promising lead compound for the development of effective SphK1 anticancer inhibitors.
研究领域:
药理学
·
癌症研究
·
药物发现
·
生物化学
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分子生物学
✓ 已验证
DOI
高影响因子
CURRENT MEDICINAL CHEMISTRY
·
2001
·Vol. 8
·期 9
·1035-1055
·
IF 4.909
Kurogi Y.,Guner O.F.
Perceiving a pharmacophore is the first essential step towards understanding the interaction between a receptor and a ligand. Once a pharmacophore is established, a beneficial use of it is 3D database searching to retrieve novel compounds that would match the pharmacophore, without necessarily duplicating the topological features of known active compounds (hence remain independent of existing patents). As the 3D searching technology has evolved over the years, it has been effectively used for lead optimization, combinatorial library focusing, as well as virtual high-throughput screening. Clearly established as one of the successful computational tools in rational drug design, we present in this review article a brief history of the evolution of this technology and detailed algorithms of Catalyst TM, the latest 3D searching software to be released. We also provide brief summary of published successes with this technology, including two recent patent applications.
研究领域:
药物化学
·
计算药理学
·
结构生物学
·
计算机辅助药物设计
·
虚拟筛选
✓ 已验证
DOI
高影响因子
Food Biophysics
·
2016
·Vol. 12
·期 1
·78-87
·
IF 1.605
Wu Zhibing,Shen Liangliang,Han Qingguo,Lu Jun,Tang Haifeng,Xu Xu,Xu Hong,Huang Fengwen,Xie Jiangfeng,He Zhendan,Zeng Zheling,Hu Zhangli
Ligupurpuroside A is a glycoside extracted from Ku-Ding tea. As extracts from Ku-Ding tea exhibit anti-inflammatory property, we hypothesize that Ligupurpuroside A may be an active compound which inhibits trypsin activity during the anti-inflammatory process. The mechanism and nature of inhibition of trypsin by Ligupurpuroside A have been studied by multi-spectroscopic method, enzyme-activity assay and molecular docking. Enzyme activity assay reveals that Ligupurpuroside A significantly inhibits the activity of trypsin through a competitive manner with an IC 50 value of 3.08 × 10 −3 mol L −1 . Fluorescence titration together with thermodynamic analysis indicate that a Ligupurpuroside A-trypsin complex is formed, and that hydrophobic force and hydrogen bonding are the main forces stabilizing the complex. UV-vis absorption, synchronous fluorescence and circular dichroism spectra show that the interaction between Ligupurpuroside A and trypsin induces conformational changes of trypsin with a decrease in the contents of α-helix and β-sheet. Finally, molecular docking further suggests that Ligupurpuroside A molecule binds within the active pocket of trypsin via hydrophobic force and hydrogen bond. Results from this study of the interaction of trypsin with its natural inhibitor should be useful to minimize the antinutritional effects and make full use of tea extracts in the food industry, and be also helpful to the design of the drugs for the diseases related to overexpression of trypsin.
研究领域:
生物化学
·
药物设计
·
食品科学
✓ 已验证
DOI
高影响因子
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6
Mengting Li,Lingyu Ma,Jiahao Lv,Zhe Zheng,Wenyu Lu,Xunkai Yin,Weijiang Lin,Ping Wang,Jian Cui,Lihong Hu,Jian Liu
Acute lung injury (ALI) is a severe respiratory disorder closely associated with the excessive activation of the NLRP3 inflammasome. Oridonin ( Ori ), a natural diterpenoid compound, had been confirmed as a specific covalent NLRP3 inflammasome inhibitor, which was completely different from that of MCC950 . However, the further clinical application of Ori was limited by its weak inhibitory activity against NLRP3 inflammasome (IC 50 = 1240.67 nM). Fortunately, through systematic structure-optimization of Ori , D6 demonstrated the enhancement of IL-1β inhibitory activity (IC 50 = 41.79 nM), which was better than the parent compound Ori . Then, by using SPR, molecular docking and MD simulation, D6 was verified to directly interact with NLRP3 via covalent and non-covalent interaction. The further anti-inflammatory mechanism studies were revealed that D6 could inhibit the activation of NLRP3 inflammasome without affecting the initiation phase of NLRP3 inflammasome activation, and D6 was a broad-spectrum and selective NLRP3 inflammasome inhibitor. Finally, D6 demonstrated a favorable therapeutic effect on LPS-induced ALI in mice model, and the potent pharmacodynamic effect of D6 was correlated with the specific inhibition of NLRP3 inflammasome activation in vivo . Thus, D6 is proved as a potent NLRP3 inhibitor, and has the potential to develop as a novel anti-ALI agent.
研究领域:
药理学
·
炎症
·
呼吸系统疾病
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药物设计
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
COLLOIDS AND SURFACES B-BIOINTERFACES
·
2024
·
IF 5.4
Yonghai Liu,Pengfei Zhang,Peiyun Lei,Yige Jin,Haoting Yu,Xingde Zhang,Yonglan Pan,Chunyan Ou,Tingming Fu
The core to the treatment of gout is the elimination of pathologic crystal, monosodium urate monohydrate (MSUM). The primary treatment available is to gradually dissolve the “culprit crystals” by lowering the blood uric acid concentration with medications, which often takes a long time and in severe cases must still be treated surgically. Herein, we developed a dynamic bionic platform based on a hydrogel composite membrane (HCM) to screen the direct facilitated solubilization of MSUM crystals by small organic molecules in bionic saturated, or even supersaturated, solutions. The customized and biologically safe (NAGA/PEGDA/NIPAM) HCM, which is consistent with the main amino acid composition of articular cartilage, well mimics the entire process of organic molecules leading to the dissolution of MSUM crystals in the joint system. With the verifications of this platform, it is shown that l-aspartic acid (ASP) significantly promotes the dissolution of MSUM crystals not only in saturated but also in supersaturated solutions. Furthermore, a novel mechanism called “crane effect” was used to explain this “dissolution effect” of ASP on MSUM, which stems from the ability of ASP to lock onto the surface of MSUM crystals through hydrogen bonding by virtue of its two carboxyl groups , and simultaneously its amino group lifts the uric acid molecules from the surface of MSUM crystals by virtue of interactions of hydrogen bonding . The results of bulk crystallization , scanning electron microscopy (SEM), powder X-diffraction (PXRD), and density-functional theory (DFT) studies are quantitatively consistent with this hypothetical "crane effect" mechanism. Hence, this HCM-based functional platform could provide entirely novel ideas and methods for drug design and screening for the treatment of pathological crystal diseases of gout.
研究领域:
生物医学工程
·
药物设计
·
晶体病治疗
✓ 已验证
DOI
高影响因子
Letters in Drug Design & Discovery
·
2018
·Vol. 15
·期 12
·1252-1258
·
IF 0.924
Meng Xianjiao,Li Shengling,Ma Wenbing,Wang Jianlong,Hu Zhiyong,Cao Duanlin
Background: Metal organic compounds have attracted considerable attention since the advent of Salvarsan, a metal organic compound for the treatment of syphilis. Ferrocene as an effective phenyl bioisostere is becoming a viable platform for drug design by virtue of its redox properties,
high lipophilicity and three-dimensional metallocene unit, which may lead to some changes in selectivity toward biological targets compared with phenyl or alkyl groups. Therefore, ferrocene seems to an appropriate candidate for improving the antioxidant activity of drugs. Methods: We
synthesized four ferrocenyl-containing curcumin analogues by introducing ferrocenyl groups into the active methylene groups to obtain higher antioxidant activity than the parent ferrocene- substituted curcumin analogues, and their antioxidant activities were evaluated in 2, 2′- azobis
(2-amidinopropane hydrochloride) (AAPH) and Cu2+/glutathione(GSH) -induced oxidation of DNA, and in trapping 2, 2′-diphenyl-1-picrylhydrazyl (DPPH), 2, 2′-azinobis(3-ethylbenzothiazoline- 6-sulfonate) cationic radicals (ABTS+•) and galvinoxyl radicals. Results: These
ferrocenyl-containing curcumin analogues can protect DNA against Cu2+/GSHinduced oxidation, and scavenge 5.7, 6.9, 5.5 and 5.3 radicals in protecting DNA against AAPHinduced oxidation. Compounds (3)~(5) can trap more DPPH, ABTS+• and galvinoxyl radicals than compound (6). The substituents
and iron atoms play an antioxidant role in ferrocenyl-containing curcumin analogues. Conclusion: The introduction of ferrocenyl group results in a higher antioxidant activity than the traditional hydroxyl-involved curcumin analogues. The ferrocenyl group is a powerful antioxidative group
that could be used to modify natural antioxidants. The electron-accepting group attaching to the phenyl-group could further increase the antioxidant activity. Ferrocene-containing curcumin analogues show higher activities in quenching radicals and protecting DNA against radical-induced oxidation.
Therefore, the introduction of ferrocenyl group into the natural antioxidant may contribute to increase the antioxidant activity.
研究领域:
药物化学
·
有机金属化学
·
药学
·
抗氧化研究
·
药物设计
✓ 已验证
DOI
高影响因子
Russian Journal of Physical Chemistry A
·
2025
·Vol. 99
·期 12
·3011-3021
·
IF 0.8
Yanfei Yang,Huang Xiaona,Wang Chenguang,Chen Xin,Zhai Cuiping
The intermolecular interactions of DNA/RNA with drugs exhibit important applications in human health and drug design. We investigated the interaction between ascorbic acid (AA), a commonly used drug in clinic, and cytosine, an important base of nucleic acids in DNA/RNA, using cyclic voltammetry (CV), 1 H NMR, density functional theory (DFT), quantum theory of atoms in molecules (QTAIM), natural bond orbital (NBO) and independent gradient model based on Hirshfeld partition (IGMH). The CV and 1 H NMR results revealed that the hydroxyl groups on the enediol of AA interacted with cytosine, making the electro-oxidation of AA difficult to occur and the downfield shift of H atoms (CH) on cytosine ring. Quantum chemistry calculations further proved the existence of O–H⋅⋅⋅N, O–H⋅⋅⋅O, C‒H⋅⋅⋅N, C–H⋅⋅⋅O, and N–H⋅⋅⋅O hydrogen bonding in the mixed system. It was found that the H atoms (H9 and H11) on enediol of AA, the N atom (N31) and carbonyl oxygen atom (O32) on the cytosine ring were the main action sites, for which H11 and N31 are more prone to be interacted with than H9 and O32.
研究领域:
物理化学
·
计算化学
·
生物有机化学
·
电化学
·
分子生物学
·
药物设计
✓ 已验证
DOI
高影响因子
LUMINESCENCE
·
2022
·Vol. 37
·期 6
·1025-1036
·
IF 2.613
Xiao Nai,Yanrong Chen,Qian Zhang,Shengyu Hao,Hongzhuan Xuan,Jie Liu
The interaction of one anticancer drug (caffeic acid phenethyl ester; CAPE) with three proteases (trypsin, pepsin and α -chymotrypsin) has been investigated with multispectral methods and molecular docking. As an active components in propolis, the findings are of great benefit to metabolism, design, and structural modification of drugs. The results show that CAPE has an obvious ability to quench the trypsin, pepsin, or α -chymotrypsin fluorescence mainly through a static quenching procedure. Trypsin has the largest binding affinity to CAPE, and α -chymotrypsin has the smallest binding affinity to CAPE. The data obtained from thermodynamic parameters and molecular docking prove that the spontaneously interaction between CAPE and each protease is mainly due to a combination of van der Waals (vdW) force and hydrogen bond (H-bond), controlled by an enthalpy-driven process. The binding force, strength, position, and the number of H-bond are further obtained from the results of molecular docking. Through ultraviolet spectroscopy, dynamic light scattering and circular dichroism experiments, the change in the protease secondary structure induced by CAPE was observed. Additionally, the addition of protease had a positive effect on the antioxidative activity of CAPE, and α -chymotrypsin has the greatest effect on the removal of 2,2-diphenyl-1-picrylhydrazyl free radicals by CAPE.
研究领域:
药理学
·
生物化学
·
药物设计
✓ 已验证
DOI
高影响因子
ARCHIV DER PHARMAZIE
·
2024
·Vol. 357
·期 5
·2300693
·
IF 4.3
Jingfang Zhai,Canhua Hao,Xiaojing Wang,Yuexing Cao,Yinbo Pan,Min Zhou,Jie Sun,Chuanyou Li
Aβ 1−42 and acetylcholinesterase (AChE) are two key therapeutic targets for Alzheimer's disease (AD). The purpose of this study is to develop a dual-target inhibitor that inhibits both of these targets by fusing the chemical structure of baicalein and donepezil. Among them, we modified the structure of baicalein to arylcoumarin, synthesized three kinds of structural compounds, and evaluated their biological activities. The results showed that compound 3b had the strongest inhibitory effect on AChE (IC 50 = 0.05 ± 0.02 µM), which was better than those of donepezil and baicalein. In addition, compound 3b has a strong ability to inhibit the aggregation of Aβ 1−42 and protect nerve cells, and it can also penetrate the blood–brain barrier well. Using a zebrafish behavioral analyzer test, it was found that compound 3b can alleviate the behavioral effects of AlCl 3 -induced zebrafish larval movement retardation, which has a certain guiding significance for simulating the movement disorders of AD patients. In summary, compound 3b is expected to become a multifunctional agent for treating and alleviating the symptoms of AD patients.
研究领域:
药理学
·
神经科学
·
药物设计
·
生物化学
✓ 已验证
DOI
高影响因子
JOURNAL OF FLUORESCENCE
·
2015
·Vol. 25
·期 2
·451-463
·
IF 1.927
Li Zhen,Li Zhigang,Yang Lingling,Xie Yuanzhe,Shi Jie,Wang Ruiyong,Chang Junbiao
In this paper, the interactions of pepsin with CYD (cytidine) or nucleoside analogs, including FNC (2′-deoxy-2′-β-fluoro-4′-azidocytidine) and CMP (cytidine monophosphate), were investigated by fluorescence, UV–visible absorption and synchronous fluorescence spectroscopy under mimic physiological conditions. The results indicated that FNC (CYD/CMP) caused the fluorescence quenching by the formation of complex. The binding constants and thermo-dynamic parameters at three different temperatures were obtained. The hydrophobic and electrostatic interactions were the predominant intermolecular forces to stabilize the complex. The F atom in FNC might weaken the binding of nucleoside analog to pepsin. Results showed that CYD was the strongest quencher and bound to pepsin with higher affinity.
研究领域:
生物化学
·
结构生物学
·
药物设计
·
分子诊断
·
酶学
✓ 已验证
DOI
高影响因子
Frontiers of Chemical Science and Engineering
·
2021
·Vol. 16
·期 7
·1090-1100
·
IF 4.204
Wen Yong-Hui,Cheng Long,Xu Tian-Ming,Liu Xing-Hai,Wu Ning-Jie
Twenty six novel pyrimidin-4-amine derivatives containing the 1,2,4-oxadiazole motif were synthesized. Their chemical structures were confirmed by 1 H nuclear magnetic resonance (NMR), 13 C NMR, and highresolution mass spectrography. The insecticidal activity results indicated that some of them possessed excellent insecticidal activity (100%) against Mythimna separate , especially for compounds 6d, 6f, 6o, 6w, 6y and 6z . These compounds exhibited no activity against the insects Aphis medicagini and Tetranychus cinnabarinus . The structure-insecticidal activity relationships are discussed. Density functional theory analysis can potentially be used to design more active compounds. These results provide useful insecticide design information for further optimization.
研究领域:
农药化学
·
计算化学
·
药物设计
·
昆虫毒理学
·
有机合成
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）