Virtual screening techniques

Virtual screening allows the scope of screening to be extended to external databases. When this is done, increasingly diverse hits can be identified. The application of virtual. screening techniques before or in parallel with HTS hclp.s to reduce the assay-to-lcad attrition rate observed from HTS. In addition, virtual screening is faster and less expensive than experimental synthesis and biological testing. 

Another group has evaluated self-organizing maps [63] and shape/ pharmacophore models [64]. They developed a new method termed SQUIRREL to compare molecules in terms of both shape and pharmacophore points. Thus from a commercial library of 199,272 compounds, 1926 were selected based on self-organizing maps trained on peroxisome proliferator-activated receptor a (PPARa) "activity islands." The compounds were further evaluated with SQUIRREL and 7 out of 21 molecules selected were found to be active in PPARa. Furthermore, a new virtual screening technique (PhAST) was developed based on representation of molecules as text strings that describe their pharmacophores [65]. 

In the following subsections we address these three points, outlining concepts of assessing the overall druglikenss of molecules, the concentration of subsets of molecules in focused libraries, and the identification of specific leads through structure-based virtual screening techniques. 

It could be argued that in the ideal case and given the power of modem computational methods, one single X-ray crystal structure of thrombin should suffice to design thrombin inhibitors with the desired properties using virtual screening" techniques. Certainly, examples of success using fhis approach are known and are... 

Virtual screening techniques require the definition of a chemistry space in order that the similarity (and distance) between compounds within the space can be quantified. Once a space has been defined, a diverse subset is one that covers the chemistry space well, whereas a focused subset is one that is restricted to a localized region within the space. A chemistry space is defined through the use of numerical descriptors, which can be calculated for molecules, as shown schematically in Fig. 1. The similarity (and... 

Various virtual screening techniques have been developed as a result of the temptation to predict the geometries of... 

Besides the use of pharmacophore fingerprints, 3D pharmacophore searches are among the most prominent 3D virtual screening techniques. Here distances between pharmacophoric features of the reference structures are compared with the respective distances in the structures of the search database. Again, these distances are conformation dependent and may be precomputed for a number of low-energy conformers in the search database to speed up the virtual screening process. This important approach is discussed in detail in a separate chapter of this book. 

In contrast, biotech companies with only a small or even without an in-house screening pool depend on virtual screening techniques to access potentially active compounds from external sources. The same is true for academic groups that in most cases neither have access to an in-house compound library nor have access to HTS facilities. 

---