Shape-based scaffold hopping

Modern assay technologies in drug design make feasible the screening of upward of 1 million compounds. The throughput of such assays enables the rapid identi- 

Experimental screening established that compound 42 shown in Fig. 8.11 disrupts ZipA-FtsZ protein-protein interaction. However, previous studies suggested potential issues with toxicity associated with this class of compounds. Additionally such amine-substituted pyridyl-pyrimidines are heavily patented in the context of kinase inhibition. Both of these factors limit the scope of the subsequent lead optimization process, to transform this compound into a viable drug. Knowledge that compound 42 was a micromolar inhibitor of ZipA-FtsZ was exploited by searching for molecules that were similar in shape. 

This approach of combining shape-matching and conformahonal analysis proved a useful complement to HTS. Some of the compounds identified by the computational screen were not detected in the original experimental screen. This was because their relative weak activity was difficult to separate from the noise of the assay. Nonetheless, these compounds had different scaffolds (i.e. were lead-hops ) compared to the previously known inhibitor. The key contribution from conformational analysis was that the newly discovered inhibitors were not found by the corresponding searches based on 2D methods. 

Embrey, K., Garcia, R., Gero, T. W., Godfrey, L., Kenny, P. W., Morley, A. D., Minshull, C. A., Pannifer, A. D., Read, J., Rees, A., Russell, D. J., Toader, D., Tucker, J. Structure-based design of protein tyrosine phospotase-lB inhibitors. Eioorg. Med. Chem. Lett. 2005, 15, 2503-2507. 

2 Burkert, U., Allinger, N. L. Molecular Mechanics, ACS Monograph 177, American Chemical Society, Washington, 1982, pp. 1-72. 

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Rush, T. S., Grant, J. A., Mosyak, L., Nicholls, A. A shape-based 3-D scaffold hopping method and its application to a bacterial protein-protein interaction. 

A further important option for ligand-based virtual screening is to perform shape comparisons that have a pronounced scaffold hopping potential. An often used method of this kind is ROCS [31] (OpenEye Scientific Sofiware, 9 Bisbee Court Suite D, Santa Fe, NM 87508, USA. Available at http //www.eyesopen.com, March 20, 2009). ROCS employs continuous functions that are derived from atom-centered Gaussians to calculate the volume overlap between two 3D structures. The use of Gaussians drastically speeds up the computational process, and ROCS is able to search even databases with millions of compounds for molecules that can adopt shapes similar to the reference compound. As in the case of 3D pharmacophore searches, the low-energy conformations must be precomputed for the search database. 

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