Compound virtual screening

Cathepsin D. The design of inhibitors of the aspartyl protease cathepsin D started from a virtual library of peptide analogs that contained the typical hydroxyethylamine isoster for the cleavable peptide bond. As the availability of starting materials would have generated a library of about 1 billion compounds, virtual screening was applied to reduce this multitude of candidate structures to a reasonable number. The backbone of a peptide... 

The term virtual screening or in silica screening is defined as the selection of compounds by evaluating their desirability in a computational model [17]. The desirability comprises high potency, selectivity, appropriate pharmacokinetic properties, and favorable toxicology. 

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

HTS data as well as virtual screening can guide and direct the design of combinatorial libraries. A genetic algorithm (GA) can be applied to the generation of combinatorial libraries [18. The number of compounds accessible by combinatorial synthesis often exceeds the number of compounds which can be syiithcsii ed... 

In general, the first step in virtual screening is the filtering by the application of Lipinski s Rule of Five [20]. Lipinski s work was based on the results of profiling the calculated physical property data in a set of 2245 compounds chosen from the World Drug Index. Polymers, peptides, quaternary ammonium, and phosphates were removed from this data set. Statistical analysis of this data set showed that approximately 90% of the remaining compounds had ... 

As the availability of crystal structures increased in the early 1990s, a number of experimental and computational methods were developed to use the structure of the protein target as a route to discover novel hit compounds. The methods include de novo design, virtual screening, and fragment-based discovery. These developments are covered in more detail in the later chapters of this book, but their main features can be summarized as follows. 

Virtual screening uses computational docking methods to assess which of a large database of compounds will fit into the unliganded structure of the target protein. Current protocols and methods can, with up to 80% success, predict the binding position and orientation of ligands that are known to bind... 

NMR 3D structure of the undecapeptide U-II generated a ligand pharmacophore hypothesis that served as query for the virtual screening of the Aventis in-house compound repository. Active leads from six different chemical classes could be identihed by the 3D search, for example, compound 17 (ECso = 400nM Fig. 16.2) [91]. 

Inosine 5 -Monophosphate Dehydrogenase. A series of 21 known inosine 5 -monophosphate dehydrogenase (IMPDH) inhibitors was used to validate a virtual screening protocol. By application of a molecular weight filter (80 < MW < 400), 3425 compounds were extracted from an in-house reagent inventory system. Docking of these compounds into a substrate-IMPDH complex 3D structure was performed with the program FlexX three... 

Shen J, Xu X, Cheng F, Liu H, Luo X, Shen J, Chen K, Zhao W, Shen X, Jiang H. Virtual screening on natural products for discovering active compounds and target information. Curr Med Chem 2003 10 1241-53. 

Molecules in real solvents can exist in one or more tautomeric forms. The use of different tautomers in calculations can lead to significant variation in the estimated log P values (Pig. 15.1). Accurate prediction of the dominant tautomer requires ah initio calculahons. Due to speed limitations such calculations are not feasible for virtual screening and prediction of large compound collections. Moreover, the interpretation of the results can also be difficult, for example, the lacton-lactim (Pig. 15. IB) is the stable form of maleic hydrazide in the gas phase but the difference between this and the dilacton form (Pig. 15.1C and D) disappears in solution... 

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