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Identification and Biological Evaluation of a Novel CLK4 Inhibitor Targeting Alternative Splicing in Pancreatic Cancer Using structure-based virtual screening

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ADVANCED SCIENCE 2025年第0期 e2416323页

作者： Yang, Chun-Lin Wu, Yi-Wen Tu, Huang-Ju Yeh, Yun-Hsuan Lin, Tony Eight Sung, Tzu-Ying Li, Mu-Chun Yen, Shih-Chung Hsieh, Jui-Hua Yu, Ming-Chin Hsieh, Sen-Yung Hsieh, Hsing-Pang Pan, Shiow-Lin Hsu, Kai-Cheng Taipei Med Univ Grad Inst Canc Biol & Drug Discovery Coll Med Sci & Technol Taipei 110301 Taiwan Taipei Med Univ Coll Med Sci & Technol PhD Program Canc Mol Biol & Drug Discovery Taipei 110301 Taiwan Natl Hlth Res Inst Inst Biotechnol & Pharmaceut Res Zhunan 350401 Miaoli Taiwan Acad Sinica Biomed Translat Res Ctr Taipei 115202 Taiwan Chinese Univ Hong Kong Shenzhen Warshel Inst Computat Biol Sch Med Shenzhen 518172 Guangdong Peoples R China Natl Inst Environm Hlth Sci Div Translat Toxicol NIH Durham NC 27709 USA Chang Gung Univ Coll Med Taoyuan 333323 Taiwan New Taipei Municipal TuCheng Hosp Built & Operated Chang Gung Med Fdn Dept Orthoped Surg New Taipei City 236043 Taiwan Chang Gung Univ Grad Inst Clin Med Sci Guishan 333423 Taoyuan Taiwan Chang Gung Mem Hosp Dept Gastroenterol & Hepatol Linkou 333423 Taoyuan Taiwan Natl Tsing Hua Univ Dept Chem Hsinchu 300044 Taiwan Taipei Med Univ TMU Res Ctr Canc Translat Med Taipei 110301 Taiwan Taipei Med Univ Wan Fang Hosp Canc Ctr Taipei 116079 Taiwan

Pancreatic cancer is an aggressive malignancy with a poor prognosis and limited treatment options. Cdc-like kinase 4 (CLK4), a kinase that regulates alternative splicing by phosphorylating spliceosome components, is implicated in aberrant splicing events driving pancreatic cancer progression. In this study, we established a computational model that integrates pharmacological interactions of CLK4 inhibitors with an improved hit rate. Through this model, we identified a novel CLK4 inhibitor, compound 150441, with a 50% inhibitory concentration (IC50) value of 21.4 nm. structure-activity relationship analysis was performed to investigate key interactions and functional groups. Kinase profiling revealed that compound 150441 is selective for CLK4. Subsequent in vitro assays demonstrated that this inhibitor effectively suppressed cell growth and viability of pancreatic cancer cells. In addition, it inhibited the phosphorylation of key splicing factors, including serine- and arginine-rich splicing factor (SRSF) 4 and SRSF6. Cell cycle analysis further indicated that the compound induced G2/M arrest, leading to apoptosis. RNA-seq analysis revealed that the compound induced significant changes in alternative splicing and key biological pathways, including RNA processing, DNA replication, DNA damage, and mitosis. These findings suggest that compound 150441 has promising potential for further development as a novel pancreatic cancer treatment.

关键词： alternative splicing CLK4 kinase inhibitor pancreatic cancer structure-based virtual screening

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Multi-stage structure-based virtual screening approach combining 3D pharmacophore, docking and molecular dynamic simulation towards the identification of potential selective PARP-1 inhibitors

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BMC CHEMISTRY 2025年第1期19卷 1-10页

作者： El Hassab, Mahmoud A. Eldehna, Wagdy M. Hassan, Ghaneya S. Abou-Seri, Sahar M. King Salman Int Univ KSIU Fac Pharm Dept Med Chem Ras Sudr 46612 South Sinai Egypt Kafrelsheikh Univ Fac Pharm Dept Pharmaceut Chem Kafrelsheikh 33516 Egypt Pharos Univ Alexandria Fac Pharm Dept Pharmaceut Chem Canal El Mahmoudia St Alexandria 21648 Egypt Cairo Univ Fac Pharm Pharmaceut Chem Dept Cairo 11562 Egypt Badr Univ Cairo BUC Sch Pharm Pharmaceut Chem Dept Cairo 11829 Egypt

Presently, humanity is confronted with a range of diseases that have high death rates, especially those linked to cancerous growths. Several enzymes and proteins have been discovered as highly attractive targets for cancer treatment. The PARP family consists of 17 members and plays a crucial role in repairing DNA damage, which enables the survival of cancer cells. PARP-1 and, to a lesser extent, PARP-2 display above 90% activity in response to DNA damage, thereby distinguishing them apart from other members of the PARP family. Elevated levels of PARP-1 were observed in many types of tumor cells, such as breast, lung, ovarian, prostate, and melanomas. In an attempt to provide a future guide for developing selective inhibitors for PARP-1 over PARP-2 to minimize the resulting side effects from PARP-2 inhibitors, we constructed a structure-based virtual screening approach (SBVS). Firstly. A 3D pharmacophore was constructed based on the interaction of the selective inhibitor compound IV. After that, a database of nearly 450,000 phthalimide-containing inhibitors was screened through the validated pharmacophore, and 165 compounds were retrieved. The retrieved compounds were docked into the active site of PARP-1 where only 5 compounds MWGS-1-5 achieved a favorable docking score than the reference IV (-16.8 Kcal/mol). Redocking of the five compounds should have excellent selectivity for PARP-1 over PARP-2, especially compound MWGS-1. Further endorsement via molecular dynamics has proven higher affinity and selectivity for MWGS-1 towards PARP-1 over PARP-2, in which PARP-1- MWGS-1 and PARP-1- MWGS-1 achieved RMSD values of 1.42 and 2.8 & Aring;, respectively.

关键词： Phthalimide Selective PARP-1 inhibitor structure-based virtual screening Pharmacophore Molecular dynamics

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Discovery of 7-hydroxy-3-(1′-methylbenzimidazol-2′-yl) coumarin as novel mitochondrial complex І inhibitor against Tetranychus cinnabarinus (Acari: Tetranychidae) via structure-based virtual screening

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PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2025年 208卷 106265页

作者： Luo, Jinxiang Li, Yunzhe Zhang, Yimeng Peng, Kejie Du, Zirong Ding, Wei Southwest Univ Coll Plant Protect Chongqing 400715 Peoples R China

Mitochondrial complex & Iukcy;is not only an important enzyme for ATP synthesis but also a promising target for acaricide discovery. However, in recent years, the complex & Iukcy;inhibitors with new scaffolds have been fewer reported. In this study, the full-length cDNA of subuits 49 kDa and PSST genes of complex & Iukcy;from Tetranychus cinnabarinus were cloned and characterized. Then, we integrated structure-based virtual screening, synthesis and acaricidal activity evaluation to discover complex & Iukcy;inhibitors with novel chemotypes. The results showed that the 49 kDa and PSST cDNA sequence of T. cinnabarinus consisted of 1443 bp and 687 bp with an open reading frame (ORF) encoding 480, 228 amino acids residues (GenBank accession number MZ172703 and MZ172704), and the highest relative expression of these two genes were nymphs and adults, respectively. The compound ZINC00042996 [7-hydroxy-3-(1 '-methylbenzimidazol-2 '-yl) coumarin] with highest acaricidal activity was obtained through virtual screening, its LC50 value was 84.85 mg/L, which was in the same order of magnitude as the LC50 value of pyridaben, and its control effect also could be comparable to that of the commercial acaricide pyridaben at 120 mg/L. The compound ZINC00042996 also exhibited excellent complex & Iukcy;inhibitory activity, the maximum inhibition rate was 47.03% for LC70 concentration after 48 h treatment. Knocking down the 49 kDa and PSST genes increased the sensitivity of T. cinnabarinus to compound ZINC00042996. Mortality of compound ZINC00042996 significantly increased to 29.49% and 16.47% in the mites fed with 49 kDa and PSST dsRNA compared with mites treated with DEPC-water. This study laid the foundation for the development of novel acaricides targeting mitochondrial complex & Iukcy;.

关键词： acaricide discovery tetranychus cinnabarinus structure-based virtual screening mitochondrial complex & Iukcy

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Discovery of a selective PI3Kα inhibitor via structure-based virtual screening for targeted colorectal cancer therapy

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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY 2025年第1期40卷 2468852页

作者： Albassam, Hussam Almutairi, Omar Alnasser, Majed Altowairqi, Faisal Almutairi, Faris Alobid, Saad King Saud Univ Coll Pharm Dept Pharmacol & Toxicol POB 2457 Riyadh 11451 Saudi Arabia

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality globally, driving an urgent need for effective therapies. A promising avenue of research focuses on the PI3K/AKT/mTOR signalling pathway, which is frequently disrupted by mutations in the PI3K alpha subunit. Our cutting-edge study employed a structure-based virtual screening of similar to 3000 compounds, leading to the discovery of F0608-0019, a highly potent and selective PI3K alpha inhibitor. F0608-0019 demonstrated remarkable efficacy in suppressing HCT116 colorectal cancer cell proliferation, with an IC50 of 12.14 mu M, while maintaining high selectivity by minimising activity against other PI3K isoforms. Advanced molecular dynamics simulations highlighted the stability of F0608-0019's binding interactions with key amino acids, such as TRP:780, ILE:932, and VAL:850, which are critical for its targeted action. These exciting findings reveal F0608-0019 as a leading candidate for innovative CRC therapies that selectively target PI3K alpha dysregulation, offering promising new possibilities for effective CRC treatment.

关键词： Colorectal cancer PI3K signalling pathway PI3K alpha inhibitor cancer drug discovery structure-based virtual screening

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structure-based virtual screening, Compound Synthesis, and Bioassay for the Design of Chitinase Inhibitors

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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2018年第13期66卷 3351-3357页

作者： Dong, Yawen Jiang, Xi Liu, Tian Ling, Yun Yang, Qing Zhang, Li He, Xiongkui China Agr Univ Coll Sci Dept Appl Chem Beijing 100193 Peoples R China Dalian Univ Technol State Key Lab Fine Chem Dalian 116024 Peoples R China Dalian Univ Technol Sch Life Sci & Biotechnol Dalian 116024 Peoples R China

Chitinases play a vital part in the molting phase of insect pests. Inhibiting their activities by the use of drug-like small chemical molecules is thought to be an efficient strategy in pesticide design and development. On the basis of the crystal structure of Of ChtI, a chitinase indispensable for the molting of the insect pest Ostrinia furnacalis (Asian corn borer), here we report a chemical fragment and five variant compounds as inhibitors of Of ChtI obtained from a library of over 200 000 chemicals by a structure-based-virtual-screening approach. The compounds were synthesized with high atom economy and tested for their. Of ChtI-inhibitory activities in a bioassay. Compound 3 showed preferential inhibitory activity with a K-i value of 1.5 mu M against Of ChtI. Analysis of the structure-activity relationships of the compounds provided insight into their interactions with the enzyme active site, which may inform future work in improving the potencies of their inhibitory activities.

关键词： chitinase inhibitors fragment structure-based virtual screening structure-activity relationship

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structure-based virtual screening and biological evaluation of novel non-bisphosphonate farnesyl pyrophosphate synthase inhibitors

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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 2020年第0期186卷 111905-000页

作者： Liu, Qingzhu Miao, Yinxing Wang, Xiaodan Lv, Gaochao Peng, Ying Li, Ke Li, Ming Qiu, Ling Lin, Jianguo Minist Hlth Jiangsu Key Lab Mol Nucl Med Jiangsu Inst Nucl Med Key Lab Nucl Med Wuxi 214063 Jiangsu Peoples R China Nanjing Med Univ Wuxi Hosp 2 Wuxi 214002 Jiangsu Peoples R China Chinese Acad Agr Sci State Key Lab Anim Nutr Inst Anim Sci Beijing 100081 Peoples R China Chinese Acad Agr Sci Publ Lab Anim Sci Beijing 100081 Peoples R China

Farnesyl pyrophosphate synthase (FPPS) is known to participate in a variety of disease-related cell signaling pathway and bisphosphonates (BPs) are served as FPPS inhibitors. However, the high polarity of BPs often induces a series of side effects, limiting their applications. In the present study, novel non-BP FPPS inhibitors were discovered by in silico screening and experimental validation. From the structure-based virtual screening (SBVS) strategy combining molecular docking, pharmacophore and binding affinity prediction, 10 hits with novel scaffolds were filtered. The inhibition activity of hits against FPPS was identified and 7 hits showed comparable or higher inhibition activity than Zoledronate. The hit VS-4 with higher lipophilicity (XlogP = 1.81) and binding affinity (K-D = 14.3 +/- 2.63 mu M) to FPPS was selected for further study on cancer cells with different FPPS expression level. Experimental results revealed that VS-4 could better target the FPPS high-expressing colon LoVo and HCT116 cancer cell lines with IC50 of 51.772 +/- 0.473 and 43.553 +/- 1.027 mu M, respectively, whereas the IC50 value against FPPS low expressing MDA-MB-231 cells was >100 mu M. The mechanism of VS-4 against colon cancer cells was investigated by flow cytometry and the results indicated that VS-4 induced cell apoptosis by increasing the intracellular reactive oxygen species (ROS) level. Taken together, the SBVS strategy could be used to discover promising non-BP FPPS inhibitors and the lead compound VS-4 might shed a light on designing more potent inhibitors as novel anticancer drugs. (C) 2019 Elsevier Masson SAS. All rights reserved.

关键词： Farnesyl pyrophosphate synthase structure-based virtual screening Non-bisphosphonate inhibitor Anticancer drug Reactive oxygen species

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structure-based virtual screening of Glycogen Synthase Kinase 3β Inhibitors: Analysis of Scoring Functions Applied to Large True Actives and Decoy Sets

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CHEMICAL BIOLOGY & DRUG DESIGN 2011年第3期78卷 378-390页

作者： Osolodkin, Dmitry I. Palyulin, Vladimir A. Zefirov, Nikolay S. Moscow MV Lomonosov State Univ Dept Chem Moscow 119991 Russia

Comparative assessment of nine different scoring functions (OpenEye and Tripos implementation) applied to structure-based virtual screening based on rigid docking of the pregenerated conformations library of glycogen synthase kinase 3 beta (GSK-3 beta) inhibitors has been carried out. The functions studied belong to the following types: Gaussian (Chemgauss3, Shapegauss), empirical (Chemscore, OEChemscore, Piecewise Linear Potential, Screen-score), force field-based (D_score and G_score), and potential of mean force (PMF_score). Overall enrichment of the large true inhibitors set against the set of true non-inhibitors, Directory of Useful Decoys (DUD), cyclin-dependent kinase 2 subset, and NCI Diversity Set was evaluated by means of ROC (receiver operating characteristic) method. According to this analysis, scoring function Chemscore leads to the best enrichment of the inhibitors whereas the best early enrichment of the actives may be obtained with the help of Chemgauss3 function as estimated by BEDROC (Boltzmann-enhanced discrimination of ROC) metrics.

关键词： chemoinformatics glycogen synthase kinase 3 beta scoring functions structure-based virtual screening

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structure-based virtual screening workflow to identify antivirals targeting HIV-1 capsid

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JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 2022年第3期36卷 193-203页

作者： Sun, Qinfang Biswas, Avik Vijayan, R. S. K. Craveur, Pierrick Forli, Stefano Olson, Arthur J. Castaner, Andres Emanuelli Kirby, Karen A. Sarafianos, Stefan G. Deng, Nanjie Levy, Ronald Temple Univ Ctr Biophys & Computat Biol Philadelphia PA 19122 USA Temple Univ Dept Chem Philadelphia PA 19122 USA Univ Texas MD Anderson Canc Ctr Inst Appl Canc Sci Houston TX 77030 USA Scripps Res Inst Dept Integrat Struct & Computat Biol La Jolla CA 92037 USA Emory Univ Dept Pediat Lab Biochem Pharmacol Sch Med Atlanta GA 30322 USA Childrens Healthcare Atlanta Atlanta GA 30322 USA Pace Univ Dept Chem & Phys Sci New York NY 10038 USA

We have identified novel HIV-1 capsid inhibitors targeting the PF74 binding site. Acting as the building block of the HIV-1 capsid core, the HIV-1 capsid protein plays an important role in the viral life cycle and is an attractive target for antiviral development. A structure-based virtual screening workflow for hit identification was employed, which includes docking 1.6 million commercially-available drug-like compounds from the ZINC database to the capsid dimer, followed by applying two absolute binding free energy (ABFE) filters on the 500 top-ranked molecules from docking. The first employs the Binding Energy Distribution Analysis Method (BEDAM) in implicit solvent. The top-ranked compounds are then refined using the Double Decoupling method in explicit solvent. Both docking and BEDAM refinement were carried out on the IBM World Community Grid as part of the FightAIDS@Home project. Using this virtual screening workflow, we identified 24 molecules with calculated binding free energies between - 6 and - 12 kcal/mol. We performed thermal shift assays on these molecules to examine their potential effects on the stability of HIV-1 capsid hexamer and found that two compounds, ZINC520357473 and ZINC4119064 increased the melting point of the latter by 14.8 degrees C and 33 degrees C, respectively. These results support the conclusion that the two ZINC compounds are primary hits targeting the capsid dimer interface. Our simulations also suggest that the two hit molecules may bind at the capsid dimer interface by occupying a new sub-pocket that has not been exploited by existing CA inhibitors. The possible causes for why other top-scored compounds suggested by ABFE filters failed to show measurable activity are discussed.

关键词： virtual screening HIV-1 capsid inhibitors structure-based virtual screening Docking Binding free energy calculation Thermal shift

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structure-based virtual screening for Dopamine D₂ Receptor Ligands as Potential Antipsychotics

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CHEMMEDCHEM 2016年第7期11卷 718-729页

作者： Kaczor, Agnieszka A. Silva, Andrea G. Loza, Maria I. Kolb, Peter Castro, Marian Poso, Antti Med Univ Lublin Dept Synth & Chem Technol Pharmaceut Subst Comp Modeling Lab Div Med AnalytFac Pharm 4A Chodzki St PL-20059 Lublin Poland Univ Eastern Finland Sch Pharm Yliopistonranta 1POB 1627 Kuopio 70211 Finland Univ Santiago de Compostela Dept Pharmacol Ctr Res Mol Med & Chron Dis CIMUS Avda Barcelona Santiago De Compostela 15782 Spain Univ Marburg Dept Pharmaceut Chem Marbacher Weg 6 D-35032 Marburg Germany Univ Tubingen Hosp Dept Internal Med 1 Div Translat Gastrointestinal Oncol Otfried Muller Str 10 D-72076 Tubingen Germany

structure-based virtual screening using a D-2 receptor homology model was performed to identify dopamine D-2 receptor ligands as potential antipsychotics. From screening a library of 6.5 million compounds, 21 were selected and were subjected to experimental validation. From these 21 compounds tested, ten D-2 ligands were identified (47.6% success rate, among them D-2 receptor antagonists, as expected) that have additional affinity for other receptors tested, in particular 5-HT2A receptors. The affinity (K-i values) of the compounds ranged from 58nm to about 24m. Similarity and fragment analysis indicated a significant degree of structural novelty among the identified compounds. We found one D-2 receptor antagonist that did not have a protonatable nitrogen atom, which is a key structural element of the classical D-2 pharmacophore model necessary for interaction with the conserved Asp(3.32) residue. This compound exhibited greater than 20-fold binding selectivity for the D-2 receptor over the D-3 receptor. We provide additional evidence that the amide hydrogen atom of this compound forms a hydrogen bond with Asp(3.32), as determined by tests of its derivatives that cannot maintain this interaction.

关键词： antipsychotics dopamine D-2 receptor dopamine D-2 receptor antagonists structure-based virtual screening

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structure-based virtual screening, molecular docking, and molecular dynamics simulation approaches for identification of new potential inhibitors of class a β-lactamase enzymes

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JOURNAL OF BIOMOLECULAR structure & DYNAMICS 2024年第11期42卷 5631-5641页

作者： Dehkordi, Maryam Khademi Hoveida, Laleh Fani, Najmeh Islamic Azad Univ Dept Biol Falavarjan Iran Islamic Azad Univ Dept Microbiol Falavarjan Iran Isfahan Univ Technol Iliya Computat Res Ctr ICRC Esfahan Iran

Bacteria are smart organisms that create drug resistance by decreasing the effect of antibiotics in different ways, such as secretion of the beta-lactamase enzymes. Finding the compounds that can act as the inhibitors of these enzymes is a great help in reducing drug resistance and treat all types of infections. In this study, using molecular docking and molecular dynamics simulation techniques, we introduced two Relebactam substructures as new inhibitors of class A beta-lactamase enzymes. Results of molecular docking show that the conformation of these two compounds in the active site of class A beta-lactamase enzymes has a good match with Relebactam and their binding affinity to enzymes is equal to or better than Relebactam. Results showed a good tendency for binding and the formation of van der Waals and hydrogen interactions between the desired compounds and the beta-lactamase enzymes. The results of the analysis of the molecular dynamics simulation trajectories showed that in the presence of the desired compounds, the second structures of the enzymes did not undergo many changes and in none of the systems, the binding of the compounds to the enzyme did not cause much instability, and in most cases made the structure stable. The hydrogen bonds were stable during the simulation time and in most cases, the new compounds formed more hydrogen bonds and had better binding affinity than Relebactam confirms the docking results. The results of this study can be helpful in designing new beta-lactamase inhibitors and new treatment methods to deal with drug resistance.

关键词： Class a beta-Lactamase enzymes relebactam structure-based virtual screening molecular docking and molecular dynamics simulation

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