Lead-hopping

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. 

There have been a number of very helpful reviews of aspects of VS in the past few years. These have focused on either specific methods, or on the field as a whole. Cramer has provided an interesting review of methods of lead-hopping, concentrating on technologies applicable to find scaffolds very different from... 

Cramer RD, Jilek RJ, Guessregen S, Clark SJ, Wendt B, Clark RD. (2004) Lead Hopping. Validation of Topomer Similarity as a Superior Predictor of Similar Biological Activities. J. Med. Chem. 47 6777-6791. 

Cramer, R D., Jilek, R J., Guessregen, S., Clark, S. J., Wendt, B., Clark, R D. (2004) Lead Hopping. Validation of topomer similarity as a superior predictor of similar biological activities. J Med Chem 47, 6777-6791. 

Basis Product, symmetric similarity score, asymmetric similarity score, lead hopping. 

Given a set of drug-like molecules as query molecules, what is the success rate of a search method in returning interesting search results not only similar to the input queries but also pertinent to lead optimization and/or lead hopping ... 

Two examples are included here to highlight how both LEAP1 and LEAP2 have been used, routinely, by chemists for idea generation and lead hopping. 

The validation studies show that the LEAP methods produce results reasonably comparable to exhaustive search and enable medicinal chemists with a practical method for the automated suggestion of synthesizable analogs for lead optimization and lead hopping. 

The latter scenario is sometimes referred to as scaffold or lead hopping [22-25]. This is a formidable challenge for the descriptor and the similarity measure. While avoiding the chemical graph and atom type-based molecular representation, the essential features required for activity have to be retained. By definition, such a task will be prone to picking out false positives and, therefore, requires a fast search in large and diverse databases together with a tunable level of similarity. 

Examples of the Use of Chemical Annotation and Pharmacophore-Based Lead-Hopping... 

Saeh, J.C., Lyne, P.D., Takasaki, B.K. and Cosgrove, D.A. (2005) Lead hopping using SVM and 3D pharmacophore fingerprints. Journal of Chemical Information and Modeling, 45,... 

P.J. (2008) Application of belief theory to similarity data fusion for use in analog searching and lead hopping. Journal of Chemical Information and Modeling, 48, 941-948. 

Martin, Y.C. and Muchmore, S. (2009) Beyond QSAR lead hopping to different structures. QSAR S, Combinatorial Science, 28, 797-801. 

Muchmore, S.W., Debe, D.A., Metz, J.T., Brown, S.P., Martin, Y.C., and Hajduk, P.J. (2008) Application of belief theory to similarity data fusion for use in analog searching and lead hopping. Journal of Chemical Information and Modeling, 48 (5), 941-948. 

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