Compound screening

In terms of environmental metrics to assess processes, it is hopefully clear that a considerable testing burden exists to assess potential environmental hazards that lead to a credible risk assessment. At a first pass, one would typically screen compounds from an environmental hazard perspective to assess their tendency for persistence, bioaccumulation and toxicity. Depending on the final application of the compoimd, one might avoid commercial production of a particular compound, or one might devise processes that would use the... 

Precipitation of compound from a DMSO stock is an issue of compound solubility in DMSO [14]. However, operationally, most organizations dissolving compounds in DMSO do not encounter problems in the solubilization process. This apparent paradox is explained by the issue of amorphous compounds. The vast majority of compounds solubilized into DMSO stocks are amorphous and inherently more soluble in DMSO (as previously discussed). The vast majority of the same compounds precipitating from DMSO are crystalline and much less soluble in DMSO (as previously discussed). The problem of compounds precipitating from DMSO occurs because so many compounds entering into screening libraries are amorphous. The precipitation of compounds from DMSO would be far less of a problem if screening compounds were entirely crystalline as they were 20 years ago. Quite simply DMSO insoluble crystalline compounds would never have been successfully dissolved in DMSO in the first place. 

We are routinely screening compounds for ability to displace 1-125 DOI from frontal cortex homogenates. As far as the CNS stimulant effects, differentiating from psychostimulants, the present model we are using is substitution in amphetamine-trained rats, in drug discrimination. We have used synaptosomes and looked at their effect on dopamine release and reuptake. But basically they are correlative models. 

In general the rate of false negatives are by definition difficult to ascertain. There are two general approaches to get a handle on false negatives. The first approach is based on what is known about the aqueous solubility of screening compounds since truly active compounds out of solution are the most common cause of false negatives. One can infer that perhaps 15% of true positives will be missed in an HTS. This inference comes from an analysis of the concordance or lack of concordance between nominal concentrations in DMSO stocks and nominal... 

It is very important to understand the goal in an HTS screen because the screening goal has a very large impact on what types of compounds should be screened, on how many compounds should be screened, and how much the screening compounds might be expected to cost. 

In a HTS campaign, typically hit compounds are ranked as a function of the number of initial positives (varying from 0.1 to 0.001% of the screened compounds), followed by those for which dose responses could be obtained (generally only 10% or less of the original hits). Of the few remaining compounds (if any),... 

Fig. 4. Structure of UK-427,857 (maraviroc), a CCR5-specific antagonist from Pfizer currently in phase III studies for HIV treatment. The original hit from the high-throughput screening, compound UK107,543, is also shown.

Several excellent reviews have appeared recently covering emerging therapies in CF, including CFTR modulators [45-47] and a collection of CFTR modulators are available through the CFF Consortium for research purposes [48]. Multiple structural classes that potentiate CFTR have been identified by screening compound libraries, natural products, and approved drugs. A subset is described below, which has proved amenable to lead optimization. 

One promising approach to identify novel CFTR corrector structural classes is to screen compounds, already developed for other indications, for their ability to correct the trafficking defect of mutant CFTR. Following this approach, glafenine hydrochloride (17), miglustat (18), and SAHA (19) were recently described as promising CFTR corrector leads. 

Screen compounds at 20 /uM final concentration in Krebs-2 extracts programmed with FF/HCV/Ren mRNA at 4 /rg/ml... 

Raeburn, P. (1999). Drug safety needs a second opinion. Business Week, Sept. 20, pp. 12-1 A. Redman, C. (1981). Screening compounds for clinically active drugs. In Statistics in the Pharmaceutical Industry. (C.R. Buncher and J. Tsay, Eds.). Marcel Dekker, New York, pp. 19 12. 

Castenholz RW, Garcia-Pichel F (2000) Cyanobacterial responses to UV-radiation. In Whitton BA, Potts M (eds) The ecology of cyanobacteria. Kluwer, Dordrecht, pp 591-611 Cockell CS, Knowland J (1999) Ultraviolet radiation screening compounds. Biol Rev 74 ... 

Karsten U, West JA (2000) Living in the intertidal zone - seasonal effects on heteiosides and sun-screen compounds in the red alga Bangia atropurpurea (Bangiales). J Exp Mar Biol Ecol 254 221-234... 

Screening compounds in mixtures rather than singly has obvious advantages of higher throughput and reduced protein consumption. There are some drawbacks, however, which can be partly alleviated by careful mixture design ... 

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