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1.
A series of thiouracil derivatives were designed, synthesized and screened for in vitro inhibition of dipeptidyl peptidase IV. The SAR study indicated the influence of substituted chemical modifications on thiouracil scaffold. Compounds 8 (IC50 = 0.32 μm ), 9 (IC50 = 0.29 μm ), and 12 (IC50 = 0.25 μm ) showed excellent dipeptidyl peptidase IV inhibition having heterocyclic substituted piperazine with acetamide linker resulted as most potent dipeptidyl peptidase IV inhibitors among all the compounds screened. Single dose (10 mg/kg) of the compounds 8 , 9 , and 12 significantly reduced glucose excursion during oral glucose tolerance test in streptozotocin‐induced diabetic rat model. The present study on substituted thiouracil derivatives shows good‐to‐moderate inhibitory potential of dipeptidyl peptidase IV enzyme. 相似文献
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Mani Sharma Monica Gupta Divya Singh Manoj Kumar Punit Kaur 《Chemical biology & drug design》2012,80(6):918-928
A series of thiazolopyrimidine derivatives was designed, synthesized and screened for in‐vitro inhibition of Dipeptidyl Peptidase IV (DPP IV). The SAR study indicated the influence of substituted chemical modifications on thiazolopyrimidine scaffold. Compound 9 (IC50 = 0.489 μm ) and 10 (IC50 = 0.329 μm ) having heterocyclic‐substituted piperazine with acetamide linker resulted as most potent DPP IV inhibitors among all the compounds screened. Single dose (10 mg/kg) of both the compounds 9 and 10 significantly reduced glucose excursion during oral glucose tolerance test in streptozotocin induced diabetic rat model. Molecular docking studies illustrated the probable binding mode and interactions of thiazolopyrimidine nucleus and its derivatives at binding site of receptor. The binding site for DPP IV is composed of active site region (catalytic triad of Ser630, Asp708 and His740) including S1 and S2 sub‐pocket. The aryl moiety of compounds 9 , 10 and 11 were observed to occupy S2 binding pocket and interacted with aromatic ring of Tyr662 and Tyr666 acquired through π‐π interaction. Thus, it is indicated that occupancy of the highly hydrophobic S2 pocket is more important for DPP IV inhibitory activity. The present study on substituted thiazolopyrimidine derivatives shows good to moderate inhibitory potential of DPP IV enzyme. 相似文献
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Yang Liu Yizhe Wu Haoshu Wu Li Tang Peng Wu Tao Liu Yongzhou Hu 《Chemical biology & drug design》2013,82(2):140-146
A novel series of (S)‐phenylalanine derivatives with a 2‐cyanopyrrolidine moiety were designed and synthesized through a rational drug design strategy. Biological evaluation revealed that most tested compounds were potent dipeptidyl peptidase 4 (DPP‐4) inhibitors; among them, the cyclopropyl‐substituted phenylalanine derivative 11h displayed the most potent DPP‐4 inhibitory activity with an IC50 value of 0.247 μ m . In addition, molecular docking analysis of the representative compounds 11h , 11k , and 15a were performed, which not only revealed the impact of binding modes on DPP‐4 inhibitory activity but also provided additional methodological values for design and optimization. 相似文献
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HIV‐1 integrase enzyme plays an important role in the life cycle of HIV and responsible for integration of virus into human genome. Here, both computational and synthetic approaches were used to design and synthesize newer HIV‐1 integrase inhibitors. Pharmacophore mapping was performed on 20 chemically diverse molecules using DISCOtech, and refinement was carried out using GASP. Ten pharmacophore models were generated, and model 2, containing four features including two donor sites, one acceptor atom, and one hydrophobic region, was considered the best model as it has the highest fitness score. It was used as a query in NCI and Maybridge databases. Molecules having more than 99% Qfit value were used to design 30 molecules bearing pteridine ring and were docked on co‐crystal structure of HIV‐1 integrase enzyme. Among these, six molecules, showing good docking score compared with the reference standards, were synthesized by conventional as well as microwave‐assisted methods. All compounds were characterized by physical and spectral data and evaluated for in vitro anti‐HIV activity against the replication of HIV‐1 (IIIB) in MT‐4 cells. The used approach of molecular docking and anti‐HIV activity data of designed molecules will provide significant insights to discover novel HIV‐1 Integrase Inhibitors. 相似文献
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Mani Sharma Monica Gupta Divya Singh Manoj Kumar Punit Kaur 《Chemical biology & drug design》2013,82(2):156-166
A series of prolyl‐fluoropyrrolidine derivatives were designed, synthesized and screened for in vitro inhibition of dipeptidyl peptidase IV. The SAR study revealed the influence of substituted chemical modifications on dipeptidyl peptidase IV inhibitory activity. Among all the compounds screened, compound 9 (IC50 = 0.83 μm ) and 10 (IC50 = 0.43 μm ) possessing aryl substituted piperazine with acetamide linker resulted as most potent dipeptidyl peptidase IV inhibitors. Both the compounds 9 and 10 resulted significant reduction in glucose excursion during oral glucose tolerance test in streptozotocin‐induced diabetic rat model at single dose of 10 mg/kg. Molecular docking studies were performed to illustrate the probable binding mode and interactions of prolyl‐fluoropyrrolidine nucleus and its derivatives at binding site of receptor. The fluoropyrrolidine moiety of prolyl‐fluoropyrrolidine derivatives occupied S1 pocket as observed in the crystal structure (PDB id: 2FJP). The compounds 9 and 10 were observed to occupy S2 binding pocket and were observed to have interaction with Arg125, Tyr547 and Ser630 acquired through hydrogen bond. The aryl moiety at piperazine ring was found to extend into the cavity and interacted with Arg358. The observed interactions signalled that occupancy of the highly hydrophobic S2 pocket is very crucial for dipeptidyl peptidase IV inhibitory activity. 相似文献
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Jinyoung Kim Ki‐sun Kim Dong‐Eun Kim Youhoon Chong 《Chemical biology & drug design》2008,72(6):585-591
We performed pharmacophore‐guided virtual screening experiments using FlexX‐Pharm to identify novel inhibitors of hepatitis C virus RNA‐dependent RNA polymerase. Pharmacophore model generated from our previous analysis of the binding modes as well as structure‐based three‐dimensional quantitative structure–activity relationship studies of aryl diketoacid analogues was used. In pharmacophore‐guided virtual screening study, among 37 447 compounds in LeadQuest chemical library, 40 compounds were selected as novel candidates of hepatitis C virus RNA‐dependent RNA polymerase inhibitors, and their biological activities were evaluated. Especially, T29 was chosen for further development. 相似文献
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Xing-Hai Liu Pei-Quan Chen Bao-Lei Wang Wei-Li Dong Yong-Hong Li Xing-Qiao Xie Zheng-Ming Li 《Chemical biology & drug design》2010,75(2):228-232
Ketol-acid reductoisomerase (KARI; EC 1.1.1.86) catalyzes the second common step in branched-chain amino acid biosynthesis. This enzyme is an important target for drug design. Based on the crystal structure of ketol-acid reductoisomerase/N-hydroxy-N-isopropyloxamate (IpOHA) complex, we have carried out high throughput receptor-based virtual screening of the ZINC/drug like database (2 000 000 compounds) to look for novel inhibitors of KARI for the first time. Some novel compounds were found to inhibit rice KARI in vitro among 15 procured compounds. This method can provide useful information for further design and discovery of KARI inhibitors. 相似文献
10.
Identification of Novel Selective Lysine‐Specific Demethylase 1 (LSD1) Inhibitors Using a Pharmacophore‐Based Virtual Screening Combined with Docking
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Chen Zhou Di Kang Yungen Xu Luyong Zhang Xiaoming Zha 《Chemical biology & drug design》2015,85(6):659-671
Lysine‐specific demethylase 1 (LSD1) plays an important role in regulating the lysine methylation at residues K4 and K9 on histone H3. High levels of LSD1 expression have been observed in several malignant tumors. In this study, we presented a pharmacophore‐based virtual screening of a moderate database of 171 143 small molecules. A pharmacophore of LSD1 inhibitors was constructed for the first time and then used to screen the compound library combined with validated molecular docking tools followed by biochemical assays, led to the identification of 9 novel LSD1 inhibitors, showing their IC50 values in a range of 2.41–101 μm . Furthermore, compound XZ 09 exhibited less inhibition against the homologous monoamine oxidase A (MAO‐A) and B (MAO‐B) displaying its moderate selectivity. Our study provides an effective virtual screening method to identify new LSD1 inhibitors and XZ09 represents a potent and selective lead compound to deserve further optimization for the treatment of LSD1 overexpressing cancers. 相似文献
11.
Xiaodong Zhang Jiang Wang Mingbo Su Zeng Li Jingya Li Jia Li Hong Liu 《Chemical biology & drug design》2012,80(6):843-852
On the basis of the enzyme‐binding features of known potent inhibitors of dipeptidyl peptidase IV, novel α‐aminoacyl‐containing proline analogs ( 8Aa–8Ak , 8Ba–8Bj , 8Ca–8Ck , and 8Da–8Di ) with the S configuration were designed, synthesized, and their activity profiled. Their structural features were determined by nuclear magnetic resonance (NMR) spectroscopy, low‐ and high‐resolution mass spectroscopy. Five compounds ( 8Aa , 8Aj , 8Ch , 8Ck , and 8Dc ) were shown to have promising inhibitory activities against dipeptidyl peptidase IV. Two of them, compounds 8Aa and 8Aj inhibited dipeptidyl peptidase IV with IC50 values of 4.56 and 8.4 μm , respectively, and displayed no inhibition at other dipeptidyl peptidase IV. The possible binding modes of compounds 6 , 7 , 8Aa , and 8Aj with dipeptidyl peptidase IV were also explored by molecular docking simulation. This study provides promising new templates for the further development of antidiabetic agents. 相似文献
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Mohammad Neaz Morshed Muhammad Muddassar Farhan Ahmad Pasha Seung Joo Cho 《Chemical biology & drug design》2009,74(2):148-158
Protein kinase CK2, also known as casein kinase‐2, has been found to be involved in cell growth, proliferation and suppression of apoptosis, which is related to human cancers. The series of compounds were identified as casein kinase‐2 inhibitors and their inhibitory activities are a function of a variation of their structures. The current study deals with the pharmacophore identification and, accordingly, the three‐dimensional quantitative structure–activity relationship model development using Pharmacophore Alignment and Scoring Engine. Several hypotheses were developed for the molecular alignments. On the basis of statistical values, the best‐fitted model was identified and the same alignment was used for 3D‐QSAR using comparative molecular field analysis/comparative molecular similarity index analysis. Both the CoMFA (R 2CV = 0.58, R 2 = 0.82 and r 2pred = 0.62) and the comparative molecular similarity index analysis (R 2CV = 0.74, R 2 = 0.98 and r 2pred = 0.81) gave reasonable results. Besides pharmacophore‐based alignment, the maximum common substructure‐based alignment was also used for the comparative molecular field analysis and comparative molecular similarity index analysis. The pharmacophore‐based alignment was more prominent and it has provided important information for the modelling of potent inhibitors. The overall study implies that a highly positive and bulky group with H‐bond donating property is desirable around the nitrogen atom adjacent to the pyrrolidine ring. 相似文献
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Using an integrated computational approach involving homology modelling, pharmacophore/structure‐based virtual screening, molecular dynamics simulations and per‐residue energy contribution, 10 compounds were proposed as potential TB inhibitors. Via validated docking calculations, binding free energy calculations showed that the proposed compounds presented better binding affinity with DNA gyrase B when compared to novobiocin. The compiled in silico approach employed in this study may serve as a useful tool in the process of the design and development of drugs, not only against TB, but also for a wide range of biological systems. 相似文献
14.
Lei Zhang Xuejian Wang Jinhong Feng Yuping Jia Fuming Xu Wenfang Xu 《Chemical biology & drug design》2012,80(6):893-901
A virtual screening approach was performed to develop novel and potent vascular endothelial growth factor receptor 2 inhibitors. The Specs database was filtered by ‘rule of five’, a pharmacophore model, and docking filter. Sixteen molecules were selected for tube formation assay, a naphthalenol group containing molecule, 12 , showed good performance in the study. In the following aortic ring assay and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay, 12 was discovered to efficiently inhibit angiogenesis and tumor cell growth. It is the first time to discover naphthalenol scaffold as potent vascular endothelial growth factor receptor 2 inhibitors. Thus, a molecular dynamic simulation process was applied to discover key features of 12 in binding to vascular endothelial growth factor receptor 2. Hydrophobic interactions were discovered to play significant role in the ligand–receptor binding. 相似文献
15.
Design,Synthesis and Biological Evaluation of 3,9‐diazatetraasteranes as Novel Matrilysin Inhibitors
Matrilysin is an ideal biological target to develop novel inhibitors because it is overexpressed in malignant tumour cells. A series of 3,9‐diazatetraasteranes was designed as inhibitors of matrilysin, which was an ideal biological target because it is responsible for aggressive malignant phenotypes and poor prognoses implicated in many cancers. Docking simulation supported the initial pharmacophore hypothesis and suggested a common interaction mechanism of 3,9‐diazatetraasteranes with the catalytic site of matrilysin. The 3,9‐diazatetraasteranes were synthesized by the photocyclization of 4‐aryl‐1,4‐dihydropyridines, and their structures were determined using 1H NMR, 13C NMR and MS. The inhibitory activities of these compounds on matrilysin were investigated in vitro using an MTT assay in A549 (small cell lung cancer) cells. The results show that the 3,9‐diazatetraasteranes can inhibit the growth of A549 tumour cells. The best IC50 value is approximately 50 μm . This result indicates that 3,9‐diazatetraasteranes will be useful pharmacological tools for the investigation of matrilysin inhibitors. 相似文献
16.
Hui‐Yuan Wang Lin‐Li Li Zhi‐Xing Cao Shi‐Dong Luo Yu‐Quan Wei Sheng‐Yong Yang 《Chemical biology & drug design》2009,73(1):115-126
In this study, 3D‐pharmacophore models of Aurora B kinase inhibitors have been developed by using HipHop and HypoGen modules in Catalyst software package. The best pharmacophore model, Hypo1, which has the highest correlation coefficient (0.9911), consists of one hydrogen‐bond acceptor, one hydrogen‐bond donor, one hydrophobic aliphatic moiety and one ring aromatic feature. Hypo1 was validated by test set and cross‐validation methods. And the specificity of Hypo1 to Aurora B inhibitors was examined with the use of selective inhibitors against Aurora B and its paralogue Aurora A. The results clearly indicate that Hypo1 can differentiate selective inhibitors of Aurora B from those of Aurora A, and the ring aromatic feature likely plays some important roles for the specificity of Hypo1. Then Hypo1 was used as a 3D query to screen several databases including Specs, NCI, Maybridge and Chinese Nature Product Database (CNPD) for identifying new inhibitors of Aurora B. The hit compounds were subsequently subjected to filtering by Lipinski’s rule of five and docking studies to refine the retrieved hits, and some compounds selected from the top ranked hits have been suggested for further experimental assay studies. 相似文献
17.
Mahmoud E. S. Soliman 《Drug development research》2013,74(5):283-295
Preclinical Research |
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Fernanda D. Botelho Marcelo C. dos Santos Arlan da S. Gonalves Kamil Kuca Martin Valis Steven R. LaPlante Tanos C. C. Frana Joyce S. F. D. de Almeida 《Toxins》2020,12(12)
Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson–Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation. 相似文献
20.
新型冠状病毒肺炎(COVID-19)全球大流行给世界健康造成巨大威胁,然而到目前为止尚没有临床证实有效的治疗方法。最近研究显示二肽基肽酶4(DPP4)可能是新型冠状病毒的功能受体,然而DPP4是否直接参与新型冠状病毒与靶细胞的黏附与感染,抑制或者调节DPP4的表达与活性能否阻止COVID-19的发生发展尚需要进一步研究。以往研究显示DPP4抑制剂具有抗炎和抗纤维化作用,因此推测DPP4抑制剂可能具有抑制COVID-19患者高炎症反应状态、改善患者肺纤维化的作用,尚需临床试验加以证实。 相似文献