In Silico Screening for Cancer Targets

与CCR/NCI的几位主要研究者合作，正在对大型小分子数据库进行<em>计算机</em>筛选，以获得许多与癌症相关的分子靶点。我们正在使用<A HREF="http://ccr.cancer.gov/staff/staff.asp?profileid=6282">CADD集团的</a>资源，包括我们的筛选<A HREF="http://ccrintra.cancer.gov/cms/annual_reports/projects/printer_friendly_report.asp?ProjID=6190">数据库</a>，以生成从商业供应商购买的化合物列表<A HREF= "http://www.chemnavigator.com/nih.asp"></a>，目的是在<em>体外</em>和/或基于细胞的测定中获得新型先导化合物。<BR>目前，我们主要致力于靶点Akt（PH结构域），与NCI癌症治疗分支的菲利普丹尼斯合作; c-Met，与CCR泌尿肿瘤分支的唐纳德·博塔罗和Terrence R合作。小伯克，药物化学实验室，CCR，NCI; HSP 90，与Len Neckers，细胞与癌症生物学分支，CCR，NCI合作; polo样激酶1的polo-Box结构域，与Kyung S. Lee，代谢实验室，CCR，NCI; Grb 2 SH 2结构域，与Terrence R.小伯克，药物化学实验室，CCR，NCI; PKC，与Peter Blumberg，癌症生物学和遗传学实验室，CCR，NCI和维克托E. Marquez，药物化学实验室，CCR，NCI;酪氨酰-DNA磷酸二酯酶（Tdp 1），与Yves Pomaly，分子药理学实验室，CCR，NCI合作;咪唑并吖啶酮DNA嵌入剂，与Sergei Tarasov，结构生物物理实验室，CCR，NCI合作。<BR>已经完成的目标包括卵磷脂视黄醇酰基转移酶（LRAT）和相关蛋白质，与Denise Simmons和Luigi DeLuca合作，前细胞致癌和肿瘤促进实验室，CCR，NCI;和ABCG 2，与Heidi Bokesch合作，分子靶标开发计划，CCR，NCI。<BR>对于Akt，c-Met和plk 1的polo-Box结构域，已经生成了初始命中集，购买了筛选样品，并由我们的合作者分析这些样品。第一个结果显示在这些测定中的每一个中许多样品的抑制活性。

In collaboration with several Principal Investigators at the CCR/NCI, <em>in silico</em> screening of large small-molecule databases are being conducted for a number of molecular targets relevant for cancer. We are using the <A HREF="http://ccr.cancer.gov/staff/staff.asp?profileid=6282">CADD Group's</a> resources, including our screening <A HREF="http://ccrintra.cancer.gov/cms/annual_reports/projects/printer_friendly_report.asp?ProjID=6190">databases</a> to generate lists of compounds to be purchased from <A HREF= "http://www.chemnavigator.com/nih.asp">commercial suppliers</a>, with the goal of obtaining novel lead compounds in <em>in vitro</em> and/or cell-based assays. <BR> Currently, we are predominantly working on the targets Akt (PH domain), in collaboration with Phillip Dennis, Cancer Therapeutics Branch, CCR, NCI; c-Met, in collaboration with Donald Bottaro, Urologic Oncology Branch, CCR, NCI, and Terrence R. Burke, Jr., Laboratory of Medicinal Chemistry, CCR, NCI; HSP90, in collaboration with Len Neckers, Cell & Cancer Biology Branch, CCR, NCI; polo-Box domain of polo-like kinase 1, in collaboration with Kyung S. Lee, Laboratory of Metabolism, CCR, NCI; Grb2 SH2 domain, in collaboration with Terrence R. Burke, Jr., Laboratory of Medicinal Chemistry, CCR, NCI; PKC, in collaboration with Peter Blumberg, Laboratory of Cancer Biology and Genetics, CCR, NCI, and Victor E. Marquez, Laboratory of Medicinal Chemistry, CCR, NCI; tyrosyl-DNA phosphodiesterase (Tdp1), in collaboration with Yves Pommier, Laboratory of Molecular Pharmacology, CCR, NCI; and imidazoacridone DNA intercalators, in collaboration with Sergei Tarasov, Structural Biophysics Laboratory, CCR, NCI. <BR> Targets for which work has been completed include lecithin retinol acyltransferase (LRAT) and related proteins, in collaboration with Denise Simmons and Luigi DeLuca, formerly Laboratory of Cellular Carcinogenesis and Tumor Promotion, CCR, NCI; and ABCG2, in collaboration with Heidi Bokesch, Molecular Targets Development Program, CCR, NCI. <BR> For Akt, c-Met, and the polo-Box domain of plk1, initial hit sets have been generated, screening samples purchased, and these samples assayed by our collaborators. First results show inhibitory activity for a number of samples in each one of these assay.