From Screen to Lead

Fundamentally, the quality of the lead structures obtained from sCTeening will depend on the nature of the compounds in the screening collection, the quality of the assay system, and the processes that are in place to progress from the assessment of active samples to the delivery of a lead series.  

Corporate screening collections now often exceed one million compounds. Ideas on the optimal size for a collection range from the suggestion that two to three million suitable compounds should deliver multiple starting points from any given screen to an estimate that up to 24 million compounds would be needed to ensure potent hits 

Compounds acquired commercially to augment screening collections are selected for diversity of structure and drug- or lead-like properties. However, since they originate in the public domain, these same compounds, or close analogs, are often present in many different saeening collections and, if identified as lead structures, do not carry a satisfactory intellectual property position without substantial structural modification.  

In the early 1990s, HTS was largely a manual process with a throughput on the order of hundreds of samples 

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Fig. 3.26. The Holdcroft-Plesch observation vessel to find the conductivity and the UV spectrum of a solution (a) plan, (b) elevation. A mixing vessel also serving as conductivity cell, and burettes, Q, Q, Q PTFE taps, D Pt wire electrodes fastened together by a lead-glass bead, E terminals from screened cables leading to D, F graded-seal soda glass-Pyrex, G cone for connection to vacuum and supply lines, 1 cm and 0.1 cm quartz cells.

J.D., Garcia, G.A., Reuter, K., Klebe, G. From hit to lead de novo design based on virtual screening hits of inhibitors of tRNA-guanine transglycosylase, a putative target of shigellosis therapy. Helv. Chim. Acta 2003, 86, 1435-1452. 

Committee on Environmental Health, American Academy of Pediatrics (AAP), Lead Poisoning From Screening to Primary Prevention, Pediatrics 92 (1993) 181. 

The sensitivity of the luminescence IP s in the systems employed here decreases with increasing x-ray energy more strongly than in the case of x-ray film. Therefore, this phenomenon must be compensated by using thicker lead front and back screens. The specific contrast c,p [1,3] is an appropriate parameter for a comparison between IP s and film, since it may be measured independently of the spatial resolution. Since the absorption coefficient p remains roughly constant for constant tube voltage and the same material, it suffices to measure and compare the scatter ratio k. Fig. 2 shows k as a function of the front and back screen thickness for the IP s for 400 keV and different wall thicknesses. The corresponding measured scatter ratios for x-ray films with 0,1 mm front and back screens of lead are likewise shown. The equivalent value for the front and back screen thicknesses is found from the intersection of the curves for the IP s and the film value. 

The antineoplastic agent mitindomide (160) in fact represents the well-known product from irradiation of maleimide in benzene [30]. The activity of this old compound was uncovered by one of the large antitumor screens maintained by the National Cancer Institute, The structure is sufficiently complex and the starting materials sufficiently available to lead one to suspect that the product is still produced photochemically. The product can be rationalized by assuming successive 1,4 and 1,2 additions to benzene. Intermediate 159a involves the 1,4 followed by 1,2 addition intermediate 159b presupposes the steps occur in the reverse order. 

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