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151.
Yen-Ling Wang Chun-Yuan Lin Kuei-Chung Shih Jui-Wen Huang Chuan-Yi Tang 《Bioorganic & medicinal chemistry letters》2013,23(23):6286-6291
Damage to DNA is caused by ionizing radiation, genotoxic chemicals or collapsed replication forks. When DNA is damaged or cells fail to respond, a mutation that is associated with breast or ovarian cancer may occur. Mammalian cells control and stabilize the genome using a cell cycle checkpoint to prevent damage to DNA or to repair damaged DNA. Checkpoint kinase 2 (Chk2) is one of the important kinases, which strongly affects DNA-damage and plays an important role in the response to the breakage of DNA double-strands and related lesions. Therefore, this study concerns Chk2. Its purpose is to find potential inhibitors using the pharmacophore hypotheses (PhModels) and virtual screening techniques. PhModels can identify inhibitors with high biological activities and virtual screening techniques are used to screen the database of the National Cancer Institute (NCI) to retrieve compounds that exhibit all of the pharmacophoric features of potential inhibitors with high interaction energy. Ten PhModels were generated using the HypoGen best algorithm. The established PhModel, Hypo01, was evaluated by performing a cost function analysis of its correlation coefficient (r), root mean square deviation (RMSD), cost difference, and configuration cost, with the values 0.955, 1.28, 192.51, and 16.07, respectively. The result of Fischer’s cross-validation test for the Hypo01 model yielded a 95% confidence level, and the correlation coefficient of the testing set (rtest) had a best value of 0.81. The potential inhibitors were then chosen from the NCI database by Hypo01 model screening and molecular docking using the cdocker docking program. Finally, the selected compounds exhibited the identified pharmacophoric features and had a high interaction energy between the ligand and the receptor. Eighty-three potential inhibitors for Chk2 are retrieved for further study. 相似文献
152.
Zhengui Huang Kejiang Lin Qidong You 《Bioorganic & medicinal chemistry letters》2013,23(14):4166-4171
As increasing drug-resistance poses an emerging threat to public health, the development of novel antibacterial agents is critical. We developed a workflow consisting of various methods for de novo design. In the workflow, 2D-QSAR model based on molecular fingerprints was constructed to extract the bioactive molecular fingerprints from a data set of DNA–gyrase inhibitors with new structure and mechanism. These fingerprints were converted into molecular fragments which were recombined to generate compound library. The new compound library was virtually screened by LigandFit and Gold docking, and the results were further investigated by pharmacophore validation and binding mode analysis. The workflow successfully achieved a potential DNA–gyrase inhibitor. It could be applied to design more novel potential DNA–gyrase inhibitors and provide theoretical basis for further optimization of the hit compounds. 相似文献
153.
Thitiporn Anunthawan Nualyai Yaraksa Santi Phosri Tinnakorn Theansungnoen Sakda Daduang Apisak Dhiravisit Sompong Thammasirirak 《Bioorganic & medicinal chemistry letters》2013,23(16):4657-4662
The principle of amino acid stretches tagged at the C terminal of Luecrocin I, which is an ultra-short antibacterial peptide, by tryptophan and arginine or lysine has been reported. The choice of amino acid type at each stretch position depends on the hydrophobic and hydrophilic regions visualized in the helical wheel pattern of Luecrocin I. Oligopeptide tagging should also consider the properties such as positive charge, hydrophobicity, the content of hydrophobic amino acids, polar angle, the properly hydrophilic and hydrophobic facets. Amidation at C terminal and lysine substitute for arginine can increase selectivity between mammalian cells (hemolytic and MTT assay) and bacterial cells tested. KT2 and RT2 which have 53% hydrophobic residues, 7 positive charges, 160° polar angle, ?0.02 (KT2) and ?0.04 (RT2) hydrophobicity were effective against S. typhi DMST 22842, S. epidermidis ATCC 12228, E. coli ATCC 25922 and V. cholerae non-O1, non-O139. The SEM images implied that the antibacterial mechanism of RT2 and KT2 may depend on concentration rather than time. Finally, RT2 and KT2 can be new antibacterial agents or may be further developed for alternative antibiotics. 相似文献
154.
Peter W. Glunz Xiaojun Zhang Yan Zou Indawati Delucca Alexandra H. Nirschl Xuhong Cheng Carolyn A. Weigelt Daniel L. Cheney Anzhi Wei Rushith Anumula Joseph M. Luettgen Alan R. Rendina Mark Harpel Gang Luo Robert Knabb Pancras C. Wong Ruth R. Wexler E. Scott Priestley 《Bioorganic & medicinal chemistry letters》2013,23(18):5244-5248
Aminoisoquinoline and isoquinoline groups have successfully replaced the more basic P1 benzamidine group of an acylsulfonamide factor VIIa inhibitor. Inhibitory activity was optimized by the identification of additional hydrophobic and hydrophilic P′ binding interactions. The molecular details of these interactions were elucidated by X-ray crystallography and molecular modeling. We also show that decreasing the basicity of the P1 group results in improved oral bioavailability in this chemotype. 相似文献
155.
Timothy A. Stammers René Coulombe Martin Duplessis Gulrez Fazal Alexandre Gagnon Michel Garneau Sylvie Goulet Araz Jakalian Steven LaPlante Jean Rancourt Bounkham Thavonekham Dominik Wernic George Kukolj Pierre L. Beaulieu 《Bioorganic & medicinal chemistry letters》2013,23(24):6879-6885
Optimization efforts on the anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors 1 and 2 resulted in the identification of multiple structural elements that contributed to improved cell culture potency. The additive effect of these elements resulted in compound 46, an inhibitor with enzymatic (IC50) and cell culture (EC50) potencies of less than 100 nanomolar. 相似文献
156.
Anne Décor Chantal Grand-Maître Oliver Hucke Jeff O’Meara Cyrille Kuhn Léa Constantineau -Forget Christian Brochu Eric Malenfant Mégan Bertrand-Laperle Josée Bordeleau Elise Ghiro Marc Pesant Gulrez Fazal Vida Gorys Michael Little Colette Boucher Sylvain Bordeleau Pascal Turcotte Annick Gauthier 《Bioorganic & medicinal chemistry letters》2013,23(13):3841-3847
We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure–activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication. 相似文献
157.
RNA is an extremely important target for the development of chemical probes of function or small molecule therapeutics. Aminoglycosides are the most well studied class of small molecules to target RNA. However, the RNA motifs outside of the bacterial rRNA A-site that are likely to be bound by these compounds in biological systems is largely unknown. If such information were known, it could allow for aminoglycosides to be exploited to target other RNAs and, in addition, could provide invaluable insights into potential bystander targets of these clinically used drugs. We utilized two-dimensional combinatorial screening (2DCS), a library-versus-library screening approach, to select the motifs displayed in a 3 × 3 nucleotide internal loop library and in a 6-nucleotide hairpin library that bind with high affinity and selectivity to six aminoglycoside derivatives. The selected RNA motifs were then analyzed using structure–activity relationships through sequencing (StARTS), a statistical approach that defines the privileged RNA motif space that binds a small molecule. StARTS allowed for the facile annotation of the selected RNA motif–aminoglycoside interactions in terms of affinity and selectivity. The interactions selected by 2DCS generally have nanomolar affinities, which is higher affinity than the binding of aminoglycosides to a mimic of their therapeutic target, the bacterial rRNA A-site. 相似文献
158.
《Molecular membrane biology》2013,30(2):184-194
AbstractMembrane proteins are intrinsically involved in both human and pathogen physiology, and are the target of 60% of all marketed drugs. During the past decade, advances in the studies of membrane proteins using X-ray crystallography, electron microscopy and NMR-based techniques led to the elucidation of over 250 unique membrane protein crystal structures. The aim of the European Drug Initiative for Channels and Transporter (EDICT) project is to use the structures of clinically significant membrane proteins for the development of lead molecules. One of the approaches used to achieve this is a virtual high-throughput screening (vHTS) technique initially developed for soluble proteins. This paper describes application of this technique to the discovery of inhibitors of the leucine transporter (LeuT), a member of the neurotransmitter:sodium symporter (NSS) family. 相似文献
159.
Masaki Wakasugi Hiroaki Gouda Tomoyasu Hirose Akihiro Sugawara Tsuyoshi Yamamoto Kazuro Shiomi Toshiaki Sunazuka Satoshi Ōmura Shuichi Hirono 《Bioorganic & medicinal chemistry》2013,21(11):3214-3220
Human acidic mammalian chitinase (hAMCase) was recently shown to be involved in the development of asthma, suggesting a possible application for hAMCase inhibitors as novel therapeutic agents for asthma. We therefore initiated drug discovery research into hAMCase using a combination of in silico methodologies and a hAMCase assay system. We first selected 23 candidate hAMCase inhibitors from a database of four million compounds using a multistep screening system combining Tripos Topomer Search technology, a docking calculation and two-dimensional molecular similarity analysis. We then measured hAMCase inhibitory activity of the selected compounds and identified seven compounds with IC50 values ?100 μM. A model describing the binding modes of these hit compounds to hAMCase was constructed, and we discuss the structure–activity relationships of the compounds we identified, suggested by the model and the actual inhibitory activities of the compounds. 相似文献
160.
以总生物碱提取率为指标,先用正交试验优化两面针的超声提取工艺,再动态过程精选提取工艺。最佳工艺条件为:复合酶预处理后,以体积分数60%乙醇(盐酸5 g/L)超声(250 W)提取3次,第1次以10倍量溶剂提取15 min,第2次以4倍量溶剂提取12 min,第3次以3倍量溶剂提取9 min,总生物碱提取率87.80%。该工艺高效、节能、省时,为工业生产奠定了实验基础。 相似文献