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J Chem Inf Model. 2013 Jul 22;53(7):1825-35. doi: 10.1021/ci4001019. Epub 2013 Jul 11.

Scaffold hopping by fragment replacement.

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Discovery Sciences Chemistry Innovation Centre, AstraZeneca R&D , Pepparedsleden 1, 43186 Mölndal, Sweden.


This work describes a data driven method for scaffold hopping by fragment replacement. A search database of scaffolds is created by cutting bonds of existing compounds in a combinatorial fashion. Three-dimensional structures of the scaffolds are then generated and made searchable based on the relative orientation of the broken bonds using an auxiliary index file. The retrieved scaffolds are ranked using volume overlap and electrostatic similarity scores. A similar approach has been used before in the program CAVEAT and others. The present work introduces a novel indexing scheme for the attachment vector geometry, which allows for fast searching. A scaffold shape descriptor is defined, which allows for queries with a single attachment vector (R-groups) and improves the shape similarity between the query and the suggested replacement fragments. The program, called Scaffold Hopping, is shown to retrieve relevant bioisosteric replacement scaffolds for a set of example queries in a reasonable time frame, making the program suitable to be used in drug design work.

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