Virtual scaffolds

The selection of building blocks is based on information derived from, for example, computational chemistry, where potential virtual ligand molecules are modeled to fit the receptor-protein binding site. Combinatorial chemistry commences with a scaffold or framework to which additional groups are added to improve the binding affinity. Compounds are prepared and later screened using HTS. In this way, many compounds are tested within a short time frame to speed up drug discovery. 

The integration of combinatorial chemistry, structure-based library design and virtual screening [268, 269] also resulted in successful applications [270, 271]. It ultimately should result in broader SAR information about directionality and physicochemical requirements of acceptable building blocks. This concept is based on feasible scaffolds for exploring protein subsites using parallel or combinatorial synthesis. 

The discovery of novel dihydrofolate reductase inhibitors by structure-based library design based on a 5-(dialkylamino)-2,4-diaminopyrimidine scaffold was reported by Wyss et al. [279] (cf Figure 4.5g). On the basis of a diaminopyrimidine core, a virtual... 

Schneider, G., Neidhart, W., Giller, T., and Schmidt, G. Scaffold-Hopping by topological pharmacophore search a contribution to virtual screening. Angeiv. Chemie. 1999, 111, 3068-3070. 

Calculation of ADME predictions is now routine and often high throughput. However, unlike many published studies in which calculated properties are validated with experimental data for a diverse collection of molecules, for virtual small-molecule libraries, there are usually no physical data to validate the predictions. Often, the molecules that are the subject of calculation are dissimilar to those molecules used to develop prediction tools. As a result, one is usually looking for trends in the prediction as a function of the selection of specific diversity reagents around a common core or scaffold. Thus, it is important to consider predicted molecular properties with care and to interpret the results with the proper level of expectation. 

Ahlstrom, M.M., Ridderstrom, M., Luthman, K. and Zamora, I. (2005) Virtual screening and scaffold hopping based on GRID molecular interaction fields. fournal of Chemical Information and Modeling, 45, 1313-1323. 

Schneider G, Neidhart W, Giller T, Schmid G. (1999) Scaffold-hopping by topological pharmacophore search A contribution to virtual screening. Angew. Chem. Int. Ed. Engl. 38 2894—2896. 

Fig. 6.4. Discovery of GGTase-I inhibitors with novel chemical scaffolds using a combination of QSAR modeling and virtual screening.

In a more recent virtual screening study, Ballester et al. reported the successful identification of novel inhibitors of ary-lamine N-acetyltransferascs using the USR algorithm (87). A computational screening of 700 million molecular conformers was conducted very efficiently. A small number of the predicted hits were purchased and experimentally tested. An impressive hit rate of 40% has been achieved. The authors also showed the ability of USR to find biologically active compounds with different chemical structures (i.e., scaffold hopping), evidenced by... 

Peterson, Y. K., Wang, X. S., Casey, P. J., Tropsha, A. (2009) Discovery of geranylgeranyltransferase-I inhibitors with novel scaffolds by the means of quantitative structure-activity relationship modeling, virtual screening, and experimental validation. J Med Chem 52, 4210-4220. 

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