Discovery screening

White, R. E., Manitpisitkul, P., Pharmacokinetic theory of cassette dosing in drug discovery screening, Drug Metab. Dispos. 2001, 29, 957-966. 

One of the driving forces to apply combinatorial chemistry in drug discovery is to accelerate lead discovery and preclinical research in order to find the next drug. It is important that these combinatorial library compounds are as pure as possible when performing lead discovery screening. At this stage,... 

PPEs in water and prevent aggregation and self-quenching [53]. Heeger and co-workers paired anionic PPV with a nonconjugated cationic polymer to form a charge-neutral complex and saw both reduction of nonspecific effects and some loss in sensitivity in protein detection [54]. Polyelectrolytes may be best used in assay schemes, such as DNA hybridization assays or drug discovery screens, where the assay conditions are well controlled and nonspecific interactions reduced or avoided. 

The use of combinatorial chemistry to produce libraries of compounds is pivotal in drug discovery. Screen hits need to be analyzed to identify the structure of the individual active component. Large numbers of samples containing only small quantities of complex mixtures require... 

Jacoby E,Schuffenhauer A, Popov M, etal. (2005) Key aspects of the Novartis compound collection enhancement project for the compilation of a comprehensive chemogenomics drug discovery screening collection. Curr. Top. Med. Cfcem. 5 397-411. 

Chapter 1 contributed from the Novartis Molecular and Library Informatics group focuses on small molecules for chemogenomics based drug discovery and summarizes the main compound categories and selection methods of relevance for the compilation of a comprehensive discovery screening collection. 

The relevance of P-gp at the BBB is considered highly important due to the low drug concentrations in the systemic circulation. The interest in transporters led to development of cell lines that overexpress them, for example, MDCK-MDRl and MDCK-MDR2. MDCK-MDRl, which overexpresses P-gp, is one of the most widely used models in early drug discovery screening [38, 39]. 

Discovery Screening Reduces Attrition by An Order of Magnitude... 

Key words Fragment-based lead discovery, screening collection, library design, computational filtering, NMR screening... 

A commonly used technique for analyzing drug discovery screening data from individuals is recursive partitioning (RP), more commonly known as trees (see, for example, Blower et al., 2002). In very recent times, efforts based on multiple trees (Svetniket al., 2003) have become the method of choice, despite the additional difficulties associated with them, because of their good predictive abilities. 

One may think of an iterative model for the preclinical discovery screening cycle. A large number of compounds are to be mined for compounds that are active for example, that bind to a particular target. The compounds may come from different sources such as vendor catalogues, corporate collections, or combinatorial chemistry projects. In fact, the compounds need only to exist in a virtual sense, because in silico predictions in the form of a model can be made in a virtual screen (Section 8) which can then be used to decide which compounds should be physically made and tested. A mapping from the structure space of compounds to the descriptor space or property space provides covariates or explanatory variables that can be used to build predictive models. These models can help in the selection process, where a subset of available molecules is chosen for the biological screen. The experimental results of the biological screen (actives and inactives, or numeric potency values) are then used to learn more about the structure-activity relationship (SAR) which leads to new models and a new selection of compounds as the cycle renews. 

Riss, T.L. et al., 2005. Selecting cell-based assays for drug discovery screening. Promega Cell Notes 13, 16-21. 

Boyd MR, Pauli KD. Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen. Drug Dev Res 1995 34 91-109. 

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