Synergistic Effects of Stereochemistry and Appendages on the Performance Diversity of a Collection of Synthetic Compounds.
Synergistic Effects of Stereochemistry and Appendages on the Performance Diversity of a Collection of Synthetic Compounds.
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DOI：
10.1021/jacs.8b07319
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发表时间：
2018-09-19
影响因子：
15
通讯作者：
Schreiber SL
中科院分区：
文献类型：
--
作者：
Melillo B;Zoller J;Hua BK;Verho O;Borghs JC;Nelson SD Jr;Maetani M;Wawer MJ;Clemons PA;Schreiber SL
生物活性的靶标和表型不可知性评估已经成为在筛选集中优先考虑支架、结构特征和合成途径的可行策略，目的是增加性能多样性。在这里，我们描述了一个功能化立体异构体氮杂环丁烷的小文库的合成及其通过“细胞绘制”的生物学注释，这是一种多路的、高含量的成像分析方法，能够以定量和无偏见的方式测量数百种化合物诱导的细胞形态的变化。使用这种方法，我们系统地比较了核心支架的生物活性，从它对细胞形态的影响，受到立体化学和附件的变化的影响的程度。我们表明，立体异构体和附属物多样化可以产生类似大小的影响，并且这些策略的同时使用导致了更广泛的生物活性抽样。
Target- and phenotype-agnostic assessments of biological activity have emerged as viable strategies for prioritizing scaffolds, structural features, and synthetic pathways in screening sets, with the goal of increasing performance diversity. Here, we describe the synthesis of a small library of functionalized stereoisomeric azetidines and its biological annotation by “cell painting,” a multiplexed, high-content imaging assay capable of measuring many hundreds of compound-induced changes in cell morphology in a quantitative and unbiased fashion. Using this approach, we systematically compare the degrees to which a core scaffold’s biological activity, inferred from its effects on cell morphology, is affected by variations in stereochemistry and appendages. We show that stereoisomerism and appendage diversification can produce effects of similar magnitude, and that the concurrent use of these strategies results in a broader sampling of biological activity.
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影响因子：
64.8
作者：
Kato N;Comer E;Sakata-Kato T;Sharma A;Sharma M;Maetani M;Bastien J;Brancucci NM;Bittker JA;Corey V;Clarke D;Derbyshire ER;Dornan GL;Duffy S;Eckley S;Itoe MA;Koolen KM;Lewis TA;Lui PS;Lukens AK;Lund E;March S;Meibalan E;Meier BC;McPhail JA;Mitasev B;Moss EL;Sayes M;Van Gessel Y;Wawer MJ;Yoshinaga T;Zeeman AM;Avery VM;Bhatia SN;Burke JE;Catteruccia F;Clardy JC;Clemons PA;Dechering KJ;Duvall JR;Foley MA;Gusovsky F;Kocken CH;Marti M;Morningstar ML;Munoz B;Neafsey DE;Sharma A;Winzeler EA;Wirth DF;Scherer CA;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
48
作者：
Caicedo JC;Cooper S;Heigwer F;Warchal S;Qiu P;Molnar C;Vasilevich AS;Barry JD;Bansal HS;Kraus O;Wawer M;Paavolainen L;Herrmann MD;Rohban M;Hung J;Hennig H;Concannon J;Smith I;Clemons PA;Singh S;Rees P;Horvath P;Linington RG;Carpenter AE
通讯作者：
Carpenter AE
影响因子：
15
作者：
Gerry CJ;Hua BK;Wawer MJ;Knowles JP;Nelson SD Jr;Verho O;Dandapani S;Wagner BK;Clemons PA;Booker-Milburn KI;Boskovic ZV;Schreiber SL
通讯作者：
Schreiber SL
DOI：
10.1073/pnas.1410933111
发表时间：
2014-07-29
影响因子：
11.1
作者：
Wawer, Mathias J.;Li, Kejie;Clemons, Paul A.
通讯作者：
Clemons, Paul A.