Drug Screening in Human Cells by NMR Spectroscopy Allows the Early Assessment of Drug Potency

Luchinat Enrico; Barbieri Letizia; Cremonini Matteo; Nocentini Alessio; Supuran Claudiu T.; Banci Lucia

摘要

Abstract > Structure‐based drug development is often hampered by the lack of in?vivo activity of promising compounds screened in?vitro, due to low membrane permeability or poor intracellular binding selectivity. Herein, we show that ligand screening can be performed in living human cells by “intracellular protein‐observed” NMR spectroscopy, without requiring enzymatic activity measurements or other cellular assays. Quantitative binding information is obtained by fast, inexpensive 1 H?NMR experiments, providing intracellular dose‐ and time‐dependent ligand binding curves, from which kinetic and thermodynamic parameters linked to cell permeability and binding affinity and selectivity are obtained. The approach was applied to carbonic anhydrase and, in principle, can be extended to any NMR‐observable intracellular target. The results obtained are directly related to the potency of candidate drugs, that is, the required dose. The application of this approach at an early stage of the drug design pipeline could greatly increase the low success rate of modern drug development. </abstract> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> <div class="translation abstracttxt"> <span class="zhankaihshouqi fivelineshidden" id="abstract"> <span>机译：</span><Abstract Type =“Main”XML：Lang =“en”> <标题类型=“main”>抽象</ title> > 由于缺乏膜渗透性或细胞内结合选择性差，缺乏缺乏有前途的化合物的缺乏的β体内活性，往往阻碍了基于结构的药物开发。在此，我们表明配体筛选可以通过“细胞内蛋白观察到的”NMR光谱在活性人体细胞中进行，而不需要酶活性测量或其他细胞测定。通过快速，廉价获得定量绑定信息 1 </ sup> H？NMR实验，提供细胞内剂量和时间依赖性配体结合曲线，从中获得与细胞渗透性和结合亲和力和选择性相关的动力学和热力学参数。将该方法应用于碳酸酐酶，原则上，可以扩展到任何NMR可观察到的细胞内靶标。得到的结果与候选药物的效力直接相关，即所需剂量。这种方法在药物设计管道早期的应用可以大大提高现代药物发展的低成功率。 </ p> </摘要> </span> <span class="z_kbtn z_kbtnclass hoverxs" style="display: none;">展开▼</span> </div> </div> <div class="record"> <h2 class="all_title" id="enpatent33" >著录项</h2> <ul> <li> <span class="lefttit">来源</span> <div style="width: 86%;vertical-align: text-top;display: inline-block;"> <a href='/journal-foreign-19011/'>《Angewandte Chemie》</a> <b style="margin: 0 2px;">|</b><span>2020年第16期</span><b style="margin: 0 2px;">|</b><span>共5页</span> </div> </li> <li> <div class="author"> <span class="lefttit">作者</span> <p id="fAuthorthree" class="threelineshidden zhankaihshouqi"> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Luchinat Enrico&option=202" target="_blank" rel="nofollow">Luchinat Enrico;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Barbieri Letizia&option=202" target="_blank" rel="nofollow">Barbieri Letizia;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Cremonini Matteo&option=202" target="_blank" rel="nofollow">Cremonini Matteo;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Nocentini Alessio&option=202" target="_blank" rel="nofollow">Nocentini Alessio;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Supuran Claudiu T.&option=202" target="_blank" rel="nofollow">Supuran Claudiu T.;</a> <a href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=Banci Lucia&option=202" target="_blank" rel="nofollow">Banci Lucia;</a> </p> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zkzz" style="display: none;">展开▼</span> </div> </li> <li> <div style="display: flex;"> <span class="lefttit">作者单位</span> <div style="position: relative;margin-left: 3px;max-width: 639px;"> <div class="threelineshidden zhankaihshouqi" id="fOrgthree"> <p>CERM—Magnetic Resonance CenterUniversità degli Studi di Firenzevia Luigi Sacconi 6 50019 Sesto Fiorentino Italy;</p> <p>CERM—Magnetic Resonance CenterUniversità degli Studi di Firenzevia Luigi Sacconi 6 50019 Sesto Fiorentino Italy;</p> <p>CERM—Magnetic Resonance CenterUniversità degli Studi di Firenzevia Luigi Sacconi 6 50019 Sesto Fiorentino Italy;</p> <p>Dipartimento NeurofarbaUniversità degli Studi di FirenzeVia Ugo Schiff 6 50019 Sesto Fiorentino Italy;</p> <p>Dipartimento NeurofarbaUniversità degli Studi di FirenzeVia Ugo Schiff 6 50019 Sesto Fiorentino Italy;</p> <p>CERM—Magnetic Resonance CenterUniversità degli Studi di Firenzevia Luigi Sacconi 6 50019 Sesto Fiorentino Italy;</p> </div> <span class="z_kbtnclass z_kbtnclassall hoverxs" id="zhdw" style="display: none;">展开▼</span> </div> </div> </li> <li > <span class="lefttit">收录信息</span> <span style="width: 86%;vertical-align: text-top;display: inline-block;"></span> </li> <li> <span class="lefttit">原文格式</span> <span>PDF</span> </li> <li> <span class="lefttit">正文语种</span> <span>eng</span> </li> <li> <span class="lefttit">中图分类</span> <span><a href="https://www.zhangqiaokeyan.com/clc/1188.html" title="应用化学">应用化学;</a></span> </li> <li class="antistop"> <span class="lefttit">关键词</span> <p style="width: 86%;vertical-align: text-top;"> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=drug design&option=203" rel="nofollow">drug design;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=drug screening&option=203" rel="nofollow">drug screening;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=in-cell NMR spectroscopy&option=203" rel="nofollow">in-cell NMR spectroscopy;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=structural biology&option=203" rel="nofollow">structural biology;</a> <a style="color: #3E7FEB;" href="/search.html?doctypes=4_5_6_1-0_4-0_1_2_3_7_9&sertext=sulfonamide&option=203" rel="nofollow">sulfonamide;</a> </p> <div class="translation"> 机译：药物设计;药物筛选;细胞内NMR光谱;结构生物学;磺胺胺; </div> </li> </ul> </div> </div> <div class="literature cardcommon"> <div class="similarity "> <h3 class="all_title" id="enpatent66">相似文献</h3> <div class="similaritytab clearfix"> <ul> <li class="active" >外文文献</li> <li >中文文献</li> <li >专利</li> </ul> </div> <div class="similarity_details"> <ul > <li> <div> <b>1. </b><a class="enjiyixqcontent" 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rel="nofollow" class="tuijian_auth tuijian_authcolor"> . 熊小椒</a> <span> . 2011</span> </span> </div> </li> </ul> <ul style="display: none;"> <li> <div> <b>1. </b><a class="enjiyixqcontent" href="/patent-detail/06120103207083.html">以斑马鱼模型进行药物筛选的方法及筛选所得药物</a> <b>[P]</b> . <span> 中国专利： CN104394856A </span> <span> . 2015-03-04</span> </div> </li> <li> <div> <b>2. </b><a class="enjiyixqcontent" href="/patent-detail/061203651449.html">一种EV71疫苗的体内效力评价方法及抗病毒药物筛选方法</a> <b>[P]</b> . <span> 中国专利： CN106554954B </span> <span> . 2020.03.03</span> </div> </li> <li> <div> <b>3. </b><a class="enjiyixqcontent" href="/patent-detail/06130442514929.html">DNA was isolated and purified, peptu00ecdeo, sequences of amino acids of human and murine sphk2, construction of recombinant DNA, host cell.Methods for producing a peptu00ecdeo of sphingosine kinase type 2 isoform of mouse and human.And to detect an agent or a drug that inhibits or promotes the activity of sphingosine kinase type 2, agent or product, methods for regulating a biological process in a mamu00ecfero,For the treatment or the improvement of a disease resulting from cell death increased or reduced cell proliferation.For the treatment or management of a disease resulting from reduced cell death or cell proliferation increased.And for the treatment or the improvement of a disease resulting from abnormal migration or motility of cells selected from the group consisted of cancer, restenose and diabetic neuropathy.Composition for the treatment or the improvement of UIMA disease resulting from cell death increased or reduced cell proliferation.Methods for screening for agents or</a> <b>[P]</b> . <span> 外国专利：  BR0109827A </span> <span> . 2004-07-06</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：分离纯化DNA，肽，人和鼠sphk2的氨基酸序列，重组DNA的构建，宿主细胞。小鼠和人2型鞘氨醇激酶2型亚型的肽的制备方法，并检测抑制或促进2型鞘氨醇激酶活性的药物或药物，药物或产物的调节方法，用于治疗哺乳动物的生物学过程的方法，用于治疗或改善由细胞死亡引起的疾病的方法，增加或减少的细胞增殖用于治疗或管理由减少的细胞死亡或细胞增殖引起的疾病，以及用于治疗或改善由癌症，再狭窄和糖尿病性神经病变组成的组中的细胞异常迁移或运动导致的疾病。用于治疗或改善由细胞死亡引起的UIMA疾病的组合物可增加或减少细胞增殖。 </span> </p> </li> <li> <div> <b>4. </b><a class="enjiyixqcontent" href="/patent-detail/06130501347700.html">Method of preparing cells exhibiting drug resistance, method of screening anticancer drugs, and anticancer drug screening kit</a> <b>[P]</b> . <span> 外国专利：  US11221326B2 </span> <span> . 2022-01-11</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：制备表现出耐药性的细胞的方法，筛选抗癌药物和抗癌药物筛查试剂盒 </span> </p> </li> <li> <div> <b>5. </b><a class="enjiyixqcontent" href="/patent-detail/06130404236523.html">METHOD OF PREPARING CELLS EXHIBITING DRUG RESISTANCE, METHOD OF SCREENING ANTICANCER DRUGS, AND ANTICANCER DRUG SCREENING KIT</a> <b>[P]</b> . <span> 外国专利：  US2019049431A1 </span> <span> . 2019-02-14</span> </div> <p class="zwjiyix translation" style="max-width: initial;height: auto;word-break: break-all;white-space: initial;text-overflow: initial;overflow: initial;"> <span>机译：制备具有耐药性的细胞的方法，筛选抗癌药的方法和抗癌药筛选工具 </span> </p> </li> </ul> </div> </div> </div> <div class="theme cardcommon" style="overflow: auto;display:none"> <h3 class="all_title" id="enpatent55">相关主题</h3> <ul id="subject"> </ul> </div> </div> </div> </div> <div class="right rightcon"> <div class="details_img cardcommon clearfix" style="margin-bottom: 10px;display:none;" > </div> </div> </div> <div id="thesis_get_original1" class="downloadBth" style="bottom: 19px;z-index: 999;" onclick="ywcd('0704028161321','4',7,2,1,'',this,24)" class="delivery" prompt="010401" title="通过人工服务将文献原文发送至邮箱" >获取原文</div> <div class="journalsub-pop-up" style="display: none"> <div class="journal-sub"> <h2>期刊订阅</h2> <img 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