Sun, 20 Jul 2008 21:39:02 BST CiteULike: neils drug http://www.citeulike.org/user/neils/tag/drug CiteULike.org en-gb Copyright © 2004-2008 citeulike.org http://www.citeulike.org/user/neils/article/2851672 <i>BMC Bioinformatics, Vol. 9, No. 1. (2008)</i><br /><br />BACKGROUND:A key goal of drug discovery is to increase the throughput of small molecule screens without sacrificing screening accuracy. High-throughput screening (HTS) in drug discovery involves testing a large number of compounds in a biological assay to identify active compounds. Normally, molecules from a large compound library are tested individually to identify the activity of each molecule. Usually a small number of compounds are found to be active, however the presence of false positive and negative testing errors suggests that this one-drug one-assay screening strategy can be significantly improved. Pooling designs are testing schemes that test mixtures of compounds in each assay, thereby generating a screen of the whole compound library in fewer tests. By repeatedly testing compounds in different combinations, pooling designs also allow for error-correction. These pooled designs, for specific experiment parameters, can be simply and efficiently created using the Shifted Transversal Design (STD) pooling algorithm. However, drug screening contains a number of key constraints that require specific modifications if this pooling approach is to be useful for practical screen designs. RESULTS:In this paper, we introduce a pooling strategy called poolHiTS (Pooled High-Throughput Screening) which is based on the STD algorithm. In poolHiTS, we implement a limit on the number of compounds that can be mixed in a single assay. In addition, we show that the STD-based pooling strategy is limited in the error-correction that it can achieve. Due to the mixing constraint, we show that it is more efficient to split a large library into smaller blocks of compounds, which are then tested using an optimized strategy repeated for each block. We package the optimal block selection algorithm into poolHiTS. The MATLAB codes for the poolHiTS algorithm and the corresponding decoding strategy are also provided. CONCLUSIONS:We have produced a practical version of STD algorithm for pooled drug screens. This pooling strategy provides both assay compression and error-correction capabilities that can both accelerate and reduce the overall cost of HTS in drug discovery. poolHiTS: A Shifted Transversal Design based pooling strategy for high-throughput drug screening Raghunandan Kainkaryam Peter Woolf doi:10.1186/1471-2105-9-256 BMC Bioinformatics, Vol. 9, No. 1. (2008) 2008-05-31T02:52:59-00:00 2008 BMC Bioinformatics 9 1 bioinformatics drug prediction screen http://www.citeulike.org/user/neils/article/2054454 <i>Curr Opin Struct Biol, Vol. 16, No. 6. (Dec 2006), pp. 676-685.</i><br /><br />To achieve high biological specificity, protein kinases and phosphatases often recognize their targets through interactions that occur outside of the active site. Although the role of modular protein-protein interaction domains in kinase and phosphatase signaling has been well characterized, it is becoming clear that many kinases and phosphatases utilize docking interactions - recognition of a short peptide motif in target partners by a groove on the catalytic domain that is separate from the active site. Docking is particularly prevalent in serine/threonine kinases and phosphatases, and is a versatile organizational tool for building complex signaling networks; it confers a high degree of specificity and, in some cases, allosteric regulation. Docking interactions in protein kinase and phosphatase networks. Attila Reményi Matthew Good Wendell Lim Curr Opin Struct Biol, Vol. 16, No. 6. (Dec 2006), pp. 676-685. 2007-12-04T03:22:10-00:00 2006 Curr Opin Struct Biol 16 6 676 685 allosteric article-predikin binding biological complex conformation design drug kinase map models molecular multiprotein phosphatase phosphoprotein protein regulation signal signaling sites structure system tertiary transduction http://www.citeulike.org/user/neils/article/2054449 <i>Science, Vol. 303, No. 5665. (Mar 2004), pp. 1800-1805.</i><br /><br />Protein kinases are targets for treatment of a number of diseases. This review focuses on kinase inhibitors that are in the clinic or in clinical trials and for which structural information is available. Structures have informed drug design and have illuminated the mechanism of inhibition. We review progress with the receptor tyrosine kinases (growth factor receptors EGFR, VEGFR, and FGFR) and nonreceptor tyrosine kinases (Bcr-Abl), where advances have been made with cancer therapeutic agents such as Herceptin and Gleevec. Among the serine-threonine kinases, p38, Rho-kinase, cyclin-dependent kinases, and Chk1 have been targeted with productive results for inflammation and cancer. Structures have provided insights into targeting the inactive or active form of the kinase, for targeting the global constellation of residues at the ATP site or less conserved additional pockets or single residues, and into targeting noncatalytic domains. Protein kinase inhibitors: insights into drug design from structure. Martin Noble Jane Endicott Louise Johnson Science, Vol. 303, No. 5665. (Mar 2004), pp. 1800-1805. 2007-12-04T03:22:10-00:00 2004 Science 303 5665 1800 1805 adenosine agents antineoplastic article-predikin as binding catalytic clinical conformation design domain drug enzyme human inhibitor kinase models molecular protein relationship signal sites structure structure-activity tertiary topic transduction trials triphosphate