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141.
Lead Generation represents a critical drug discovery phase where chemical starting points and their respective mechanism of action, quality, and potential liabilities are largely predefined. Recent advances such as DNA-encoded libraries or fragment-, chemical biology-, and virtual screening-based approaches are today as common as traditional High Throughput Screening. Innovations in characterizing lead quality have allowed more informed decision-making by discovery teams. The key challenge today is to individually tailor the right mix of methods for each project to facilitate data integration with the purpose of creating multiple high-quality lead series, ultimately translating to reduced chemistry-related pipeline attrition. 相似文献
142.
K. Kaseja S. Mucha J. Yates E. Smith G. Banos J. Conington 《Animal : an international journal of animal bioscience》2022,16(3):100468
Genomic variants such as Single Nucleotide Polymorphisms and animal pedigree are now used widely in routine genetic evaluations of livestock in many countries. The use of genomic information not only can be used to enhance the accuracy of prediction but also to verify pedigrees for animals that are extensively managed using natural mating and enabling multiple-sire mating groups to be used. By so doing, the rate of genetic gain is enhanced, and any bias associated with incorrect pedigrees is removed. This study used a set of 8 764 sheep genotypes to verify the pedigree based on both the conventional opposing homozygote method as well as a novel method when combined with the inclusion of the genomic relationship matrix (GRM). The genomic relationship coefficients between verified pairs of animals showed on average a relationship of 0.50 with parent, 0.25 with grandparent, 0.13 with great grandparent, 0.50 with full-sibling and 0.27 with half-sibling. Minimum obtained values from these verified pairs were then used as thresholds to determine the pedigree for unverified pairs of animals, to detect potential errors in the pedigree. Using a case study from a population partially genotyped UK sheep, the results from this study illustrate a powerful way to resolve parentage inconsistencies, when combining the conventional ‘opposing homozygote’ method using genomic information together with GRM for pedigree checking. In this way, previously undetected pedigree errors can be resolved. 相似文献
143.
The retention of whole-cell bioactivity is essential to the biocatalysis in reaction mixture containing organic compounds
for the preparation of products in the pharmaceutical fine chemicals and food industries. A Quantitative Structure-Activity
Relationship (QSAR) toxicity model for determination of whole-cell bioactivity was developed on the basis of receptor theory.
And the glycolysis activity retention of baker's yeast in the presence of organic compounds was investigated in this study.
Based on the fitting of the QSAR model to experimental data obtained in this study and in previous literatures, the regression
analysis indicated that calculated values with this model were consistent with experimental data. Comparison of experimental
data to the modeled curves suggests good predictive capabilities of the model for determination of whole-cell bioactivity. 相似文献
144.
目的:探讨油田野外作业人员职业紧张与生理健康及心理障碍的关系。方法:采用分层整群抽样抽取1862例油田野外作业人员,对所有油田野外作业人员发放问卷进行调查,有效回收1546份调查问卷,回收率83.03%。采用职业紧张量表修订表统计油田野外作业人员职业紧张发生状况,其中重度紧张者571例、中度紧张者590例、正常者385例,采用症状自评量表-90(SCL-90)对不同程度职业紧张人员进行心理健康状况评估,采用慢性非传染性疾病调查表问卷统计不同程度职业紧张人员的慢性疾病患病率,采用Logistic回归分析油田野外作业人员心理障碍影响因素。结果:重度紧张者、中度紧张者SCL-90各项评分均高于正常者,且重度紧张者SCL-90各项评分高于中度紧张者(P0.05)。油田野外作业人员心理障碍与其年龄、工龄无关(P0.05),男性、有倒班、吸烟、饮酒情况的油田野外作业人员心理障碍发生率高于女性、无倒班、吸烟、饮酒情况的油田野外作业人员(P0.05)。Logistic回归分析显示,男性、有倒班、吸烟、饮酒情况是影响油田野外作业人员发生心理障碍的危险因素。重度紧张者、中度紧张者的慢性疾病患病率均高于正常者(P0.05)。结论:男性、有倒班、吸烟、饮酒情况的油田野外作业人员心理障碍发生率较高,且油田野外作业人员职业紧张程度越高,越容易增加心理障碍以及慢性疾病的发生风险。 相似文献
145.
Bruce J. Melancon Michael R. Wood Meredith J. Noetzel Kellie D. Nance Eileen M. Engelberg Changho Han Atin Lamsal Sichen Chang Hyekyung P. Cho Frank W. Byers Michael Bubser Carrie K. Jones Colleen M. Niswender Michael W. Wood Darren W. Engers Dedong Wu Nicholas J. Brandon Mark E. Duggan Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2017,27(11):2296-2301
This letter describes the further chemical optimization of the 5-amino-thieno[2,3-c]pyridazine series (VU0467154/VU0467485) of M4 positive allosteric modulators (PAMs), developed via iterative parallel synthesis, culminating in the discovery of the non-human primate (NHP) in vivo tool compound, VU0476406 (8p). VU0476406 is an important in vivo tool compound to enable translation of pharmacodynamics from rodent to NHP, and while data related to a Parkinson’s disease model has been reported with 8p, this is the first disclosure of the optimization and discovery of VU0476406, as well as detailed pharmacology and DMPK properties. 相似文献
146.
首次对鹟科(Muscicapidae)画眉亚科三种鸟----画眉(Garrulax canorus)、红嘴相思鸟(Leiothrix lutea)、棕头雅雀(Paradoxornis webbiana);鸫亚科的乌鸫(Turdinae merula)线粒体DNA的12S rRNA基因片段的DNA序列进行了测定,并与北美画眉亚科弯嘴鹛属(Pomatostomus)的灰冠弯嘴鹛(P.temporalis)同源序列进行分析比较并构建分子进化树。实验结果与传统形态学论述存在一定的差异,与同工酶研究结果相同:画眉与红嘴相思鸟的亲缘关系最近,棕头鸦雀较乌鸫与画眉亚科的关系更近,为将其置于画眉亚科提供了分子证据。
Abstract:The classfication on Muscicapinae disturbed us for a long time.The important thing is to find an appropriate character to resolve it.It is the first time that we testified the mitochondrial 12S rRNA gene fragment sequence of four birds (G.canorus,L.lutea,P.webbianus and T.merula-owing to Muscicapinae) and aligned with the same sequence of P.temporalis.Using the mitochondrial 12S rRNA sequences date,we built phylogenetic trees.The results indicated that that the relationship between Garrulax canorus and Leiothrix lutea in the four birds was closer which is congruent with morphology.According to the results of isoenzyme and DNA sequencing data,we can draw a conclusion that Paradoxornis webbianus has closer relationship to Timaliinae than that of Turdus merula,and that putting Paradoxonithinae to Timaliinae was reasonable. 相似文献
147.
The electrophoresis analysis of isozymes of Arachis show a very close relationship among four types of cultispecies (A. hypogaea) and A. monticola, the tetraploid wild species is a related species. Among the five diploid wild species of Arachis Section, both A. cardenasii with A genome and A. batizocoi with B genome are found to be relatively nearer to cultis'pecies than A. correntina, A. stenosperma and A. villosa, while A. rigonii of Erectoides Section and A. pusilla of Triseminala Section are the distant species. 相似文献
148.
149.
Andrew S. Felts Katrina A. Bollinger Christopher J. Brassard Alice L. Rodriguez Ryan D. Morrison J. Scott Daniels Anna L. Blobaum Colleen M. Niswender Carrie K. Jones P. Jeffrey Conn Kyle A. Emmitte Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2019,29(1):47-50
This letter describes the further chemical optimization of VU0424238 (auglurant), an mGlu5 NAM clinical candidate that failed in non-human primate (NHP) 28?day toxicology due to accumulation of a species-specific aldehyde oxidase (AO) metabolite of the pyrimidine head group. Here, we excised the pyrimidine moiety, identified the minimum pharmacophore, and then developed a new series of saturated ether head groups that ablated any AO contribution to metabolism. Putative back-up compounds in this novel series provided increased sp3 character, uniform CYP450-mediated metabolism across species, good functional potency and high CNS penetration. Key to the optimization was a combination of matrix and iterative libraries that allowed rapid surveillance of multiple domains of the allosteric ligand. 相似文献
150.
Russell AL Kennedy AM Spuches AM Gibson WS Venugopal D Klapper D Srouji AH Bhonsle JB Hicks RP 《Chemistry and physics of lipids》2011,(8):740-758
Circular Dichroism (CD), isothermal calorimetry (ITC) and calcein fluorescence leakage experiments were conducted to provide insight into the mechanisms of binding of a series of antimicrobial peptides containing unnatural amino acids (Ac-XF-Tic-Oic-XK-Tic-Oic-XF-Tic-Oic-XK-Tic-KKKK-CONH2) to zwitterionic and anionic micelles, SUVs and LUVs; where X (Spacer# 1) is either Gly, β-Ala, Gaba or 6-aminohexanoic acid. It is the intent of this investigation to correlate these interactions with the observed potency and selectivity against several different strains of bacteria. The CD spectra of these compounds in the presence of zwitterionic DPC micelles and anionic SDS micelles are very different indicating that these compounds adopt different conformations on binding to the surface of anionic and zwitterionic membrane models. These compounds also exhibited very different CD spectra in the presence of zwitterionic POPC and anionic mixed 4:1 POPC/POPG SUVs and LUVs, indicating the formation of different conformations on interaction with the two membrane types. This observation is also supported by ITC and calcein leakage data. ITC data suggested these peptides interact primarily with the surface of zwitterionic LUVs and was further supported by fluorescence experiments where the interactions do not appear to be concentration dependent. In the presence of anionic membranes, the interactions appear more complex and the calorimetric and fluorescence data both imply pore formation is dependent on peptide concentration. Furthermore, evidence suggests that as the length of Spacer# 1 increases the mechanism of pore formation also changes. Based on the observed differences in the mechanisms of interactions with zwitterionic and anionic LUVs these AMPs are potential candidates for further drug development. 相似文献