Drug screening process

Several experimental systems to check the inhibition potency of bile add transport have been characterized. Using sandwich-cultured human hepatocytes, bosentan, cyclosporin A, CI-1034 (endothelin-A receptor antagonist), glyburide, erythromycin estolate, and troleandomycin could inhibit the taurocholate efflux to the bile pocket [234]. Moreover, Mita et al. [235] construded NTCP/BSEP double-transfeded cells and some cholestasis-induced compounds inhibited both the NTCP-mediated uptake and the BSEP-mediated efflux of taurocholate. Then, they have found fluorescent bile acids whose transcellular transport was dearly observed, which may be used for the rapid identification of inhibitors of NTCP and BSEP in drug screening process [235]. 

A major consideration in screening is the detection capability of the screen for both false negatives (lack of detection of an active drug) and propensity to find false positives (detection of a response to the compound not due to therapeutic activity of interest). Ostensibly, false positives might not be considered a serious problem in that secondary testing will detect these and they do not normally interfere with the drug discovery process. 

The drug discovery process can be divided into four subsets acquisition of chemical drug candidates, pharmacodynamic testing of large numbers of compounds (screening), and the optimization of pharmacokinetic and pharmaceutical properties. 

Of course, class 4 is not valuable in medicinal chemistry. Such compounds have to be excluded from drug discovery processes as early as possible. At present, there are computer alert programs based on the Rule-of-5 or similar approaches that are used in preliminary screening to select and exclude compounds of class 4 [71]. Van de Waterbeemd indicated in 1998 that the four BCS classes of drugs can be determined solely by considering physicochemical descriptors such as molecular weight and PSA [72]. However, as mentioned in this chapter, those descriptors are too crude for the quantitative description of molecular size and H-bonding ability. 

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