共查询到20条相似文献,搜索用时 31 毫秒
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We present a novel computer algorithm, called GLARE (Global Library Assessment of REagents), that addresses the issue of optimal reagent selection in combinatorial library design. This program reduces or eliminates the time a medicinal chemist spends examining reagents which a priori cannot be part of a "good" library. Our approach takes the large reagent sets returned by standard chemical database queries and produces often considerably reduced reagent sets that are well-behaved with respect to a specific template. The pruning enforces "goodness" constraints such as the Lipinski rule of five on the product properties such that any reagent selection from the resulting sets produces only "good" products. The algorithm we implemented has three important features: (i) As opposed to genetic algorithms or other stochastic algorithms, GLARE uses a deterministic greedy procedure that smoothly filters out nonviable reagents. (ii) The pruning method can be biased to produce reagent sets with a balanced size, conserving proportionally more reagents in smaller sets. (iii) For very large combinatorial libraries, a partitioning scheme allows libraries as large as 10(12) to be evaluated in 0.25 s on an IBM AMD Opteron processor. This algorithm is validated on a diverse set of 12 libraries. The results that we obtained show an excellent compliance to the product property requirements and very fast timings. 相似文献
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Synthesis of flavonoid analogues as scaffolds for natural product-based combinatorial libraries 总被引:2,自引:0,他引:2
The design and synthesis of flavonoid analogues as combinatorial scaffolds is reported. Using commercially available materials, we synthesized chalcones with fluoro and carboxy groups. Nitration of these compounds generated highly functionalized flavonoid scaffolds with an o-fluoronitrobenzene template. Subsequent cyclizations of these chalcones resulted in the formation of several flavone and flavonone scaffolds. One of the flavonones was chosen as the scaffold to synthesize flavonoid derivatives on the solid phase. A series of flavonoid derivatives were obtained in high yields, which demonstrates that these highly functionalized scaffolds can be used in the synthesis of natural product-based combinatorial libraries for drug discovery. 相似文献
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Yasri A Berthelot D Gijsen H Thielemans T Marichal P Engels M Hoflack J 《Journal of chemical information and computer sciences》2004,44(6):2199-2206
REALISIS is a software system for reagent selection, library design, and profiling, developed to fit the workflow of bench chemists and medicinal chemists. Designed to be portable, the software offers a comprehensive graphical user interface and rapid, integrated functionalities required for reagent retrieval and filtering, product enumeration, and library profiling. REALISIS is component-based, consisting of four main modules: reagent searching; reagent filtering; library enumeration; and library profiling. Each module allows the chemist to access specific functionalities and diverse filtering and profiling mechanisms. By implementing the entire process of reagent selection, library design, and profiling and by integrating all the necessary functionalities for this process, REALISIS cuts the time required to design combinatorial and noncombinatorial libraries from several days to a few hours. 相似文献
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Sprous DG Lowis DR Leonard JM Heritage T Burkett SN Baker DS Clark RD 《Journal of combinatorial chemistry》2004,6(4):530-539
Products from combinatorial libraries generally share a common core structure that can be exploited to improve the efficiency of virtual high-throughput screening (vHTS). In general, it is more efficient to find a method that scales with the total number of reagents (Sigma growth) rather with the number of products (Pi growth). The OptiDock methodology described herein entails selecting a diverse but representative subset of compounds that span the structural space encompassed by the full library. These compounds are docked individually using the FlexX program (Rarey, M.; Kramer, B.; Lengauer, T.; Klebe, G. J. Mol. Biol. 1995, 251, 470-489) to define distinct docking modes in terms of reference placements for combinatorial core atoms. Thereafter, substituents in R-cores (consisting of the core structure substituted at a single variation site) are docked, keeping the core atoms fixed at the coordinates dictated by each reference placement. Interaction energies are calculated for each docked R-core with respect to the target protein, and energies for whole compounds are calculated by finding the reference core placement for which the sum of corresponding R-core energies is most negative. The use of diverse whole compounds to define binding modes is a key advantage of the protocol over other combinatorial docking programs. As a result, OptiDock returns better-scoring conformers than does serially applied FlexX. OptiDock is also better able to find a viable docked pose for each library member than are other combinatorial approaches. 相似文献
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It is practically impossible in a short period of time to synthesize and test all compounds in any large exhaustive chemical library. We discuss rational approaches to selecting representative subsets of virtual libraries that help direct experimental synthetic efforts for both targeted and diverse library design. For targeted library design, we consider principles based on the similarity to lead molecules. In the case of diverse library design, we discuss algorithms aimed at the selection of both diverse and representative subsets of the entire chemical library space. We illustrate methodologies with several practical examples. 相似文献
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Mosley RT Culberson JC Kraker B Feuston BP Sheridan RP Conway JF Forbes JK Chakravorty SJ Kearsley SK 《Journal of chemical information and modeling》2005,45(5):1439-1446
Reagent Selector is an intranet-based tool that aids in the selection of reagents for use in combinatorial library construction. The user selects an appropriate reagent group as a query, for example, primary amines, and further refines it on the basis of various physicochemical properties, resulting in a list of potential reagents. The results of this selection process are, in turn, converted into synthons: the fragments or R-groups that are to be incorporated into the combinatorial library. The Synthon Analysis interface graphically depicts the chemical properties for each synthon as a function of the topological bond distance from the scaffold attachment point. Displayed in this fashion, the user is able to visualize the property space for the universe of synthons as well as that of the synthons selected. Ultimately, the reagent list that embodies the selected synthons is made available to the user for reagent procurement. Application of the approach to a sample reagent list for a G-protein coupled receptor targeted library is described. 相似文献