Computational filtering

In general, the described techniques provide an effective, flexible, and relatively fast solution for library design based on analysis of bioscreening data. The quantitative relationships, based on the assessment of contribution values of various molecular descriptors, not only permit the estimation of potential biological activity of candidate compounds before synthesis but also provide information concerning the modification of the structural features necessary for this activity. Usually these techniques are applied in the form of computational filters for constraining the size of virtual combinatorial libraries and... 

Ekins S, Berbaum J, Harrison RK. Generation and validation of rapid computational filters for Cyp2D6 and Cyp3A4. Drug Metab Dispos 2003 31 1077-80. 

Fig. 7. (a) Crystals of E. colt 70 S ribosomes, (b) and (c) Electron micrographs of sections through three-dimensional crystals shown in (a) in two orthogonal directions (Wittmann et al., 1982). (d) and (e) Crystals and computed filtered image of a section through a crystal of Bacillus stearothermophilus 50 S ribosomal subunits (Yonath et al., 1982a,b Leonard et al., 1983). (d) and (e) are related to two different crystal forms. Reproduced with permission from Wittmann (1983). 

Guba W, Roche O. (2004) Computational filters in lead generation Targeting drug-hke chemotypes. In H Kubini, G Muller (eds), Chemogenomics in Drug Discovery — A Medicinal Chemistry Perspective, pp. 325-339. Wiley-VCH, Weinheim. 

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

Jennings, A., and Tennant, M. (2005). Discovery strategies in a biopharmaceutical startup maximising your chances of success using computational filters. Curr. Pharm. Des. 11, 335-344. 

These results indicate that classification methods could be very effective computational filters if used prior to experimental testing. However, what is apparent from many of the published studies is that prospective use and follow-up testing of compounds suggested is very limited to date. 

Computational Filters in Lead Generation Targeting Drug-like Chemotypes... 

In conclusion, the quest for novel chemotypes is a long, expensive process. Therefore, the statistical relevance, predictivity range, and stability of computational filters need to be scrutinized in order to prevent a potential lead series from being rejected for the wrong reason. 

Chemical libraries are the topic of the final section and cover chemogenomics in compound library and template design for GPCRs (T. R. Webb), computational filters in lead generation (W. Guba), navigation in chemical space (G. Schneider... 

Improbability of docked binding mode. Fast docking tools cannot produce reasonable solutions for all compounds. Often even some high-scoring compounds are found to be docked to the outer surface of the protein. Computational filters help to detect such situations. 

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