In-house libraries

Virtual screening assists the selection of compounds for screening in-house libraries and compounds from external suppliers. Two different strategies can be applied ... 

SB-366791 (18) emerged from screening an in-house library as a potent competitive inhibitor of both hTRPVl and rTRPVl, endowed with superior target selectivity compared to capsazepine [84]. Structure-activity relationships of SB-366791 remain to be reported. 

The hit, SB-452533, (23a) was discovered by HTS of an in-house library at GSK [86]. Compound (23a) could potently and reversibly inhibit activation of TRPVl by capsaicin, low pH and heat. Quaternization of (23a) by N-methylation afforded (24), unlikely to cross the cell membranes, but that eould nevertheless retain a certain degree of inhibitory activity on TRPVl activation. When (24) was applied intracellularly, no activity could be detected. The binding of eaps-aicin to TRPVl has traditionally been considered intracellular, but this and other observations actually suggest a more complex situation. 

Finally, there is great value in providing access to contemporary and archived technical journals and trade magazines to technical service professionals. This can be achieved in a number of ways, whether by generation of an in-house library, use of nearby university or governmental facilities, support of individual subscriptions, or some combination of the above. Internet access to on-line journals is also valuable. 

Next, we used an in-house library design software (see details in Chapter 15) to enumerate the virtual libraries and then calculated various physical properties. Products were removed from consideration if MW is > 300, number of rotatable bonds > 3, and ClogP > 3. For solubility, two in-house model calculations were applied as filters turbidimetric >10 mg/mL and thermodynamic solubility >100 xM. The resulting cherry-picked library was then reviewed by NMR spectroscopists to remove compounds with possible artifacts, likely to be insoluble, or likely to be false positive. These included some conjugated systems and compounds with likelihood of indistinct NMR spectra. 

Partitioning methods are well suited to database comparisons since the definitions of the partitions are data independent. The PDQ partitioning approach has been used to compare in-house libraries at RPR [24], The total number of pharmacophores contained within each of three different libraries was calculated and the number of pharmacophores that are common to any... 

P-gp inhibitors from our in-house library C P-gp substrates from the literature D chemicals), models derived by using reference sets related to the target P-gp (B, C) gave highest internal (leave-one-out cross-validation) and external (test set) predictivity [49]. 

Spectra obtained from both phases were interpreted on a MassLib data system (Max Planck Institute, Germany), using IFF in-house libraries and commercial Wiley 7, NIST 98 and other libraries. The identification of flavor components was confirmed by interpretation of MS data and by relative GC retention indices based on a calibration with ethyl esters. 

Among them, a typical illustration of the SOSA approach is shown by the development of a selective ligand for the endotheline ETa receptors by scientists from Bristol-Myers-Squibb. " Starting from an in-house library, the antibacterial compound sulfathiazole (Fig. 5.13) was an initial, but weak, hit (IC50 = 69 p,M). Testing of related sulfonamides identified the more potent sulfisoxazole (IC50 = 0.78 xM). Systematic variations led finally to the potent and selective... 

In a second example, researchers at Hoffmann-LaRoche in Basel applied a program they developed called CATS (Chemically Advanced Template Search) to mibefradil, a known 1.7 pM calcium channel blocker. In-house libraries were virtually screened using this pharmacophore search and the highest-ranking molecules went into a real, cellular Ca influx assay. The best of... 

Calculation of a retention index based on a set of standards that can be compared with published or in-house library data. For a homologous series of comp>ounds, the logarithm of the retention time is directly proprortional to the number of carbon atoms. The Kovats system, based on the homologous... 

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