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Article

Exhaustive de novo Design of Low-Molecular-Weight Fragments Against the ATP-Binding Site of DNA-Gyrase

Stuart Firth-Clark,* Nikolay P. Todorov, Ian L. Alberts, Anthony Williams, Timothy James,^† and Philip M. Dean

De Novo Pharmaceuticals Ltd., Compass House, Vision Park, Histon, Cambridge CB4 9ZR, U.K.

J. Chem. Inf. Model., 2006, 46 (3), pp 1168–1173

DOI: 10.1021/ci050338i

Publication Date (Web): January 12, 2006

Corresponding author phone: +44 1223 238000; fax: +44 1223 238088; e-mail: stuart.firth-clark@denovopharma.com.

†

Present address: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.

Abstract

We present a de novo design approach to generating small fragments in the DNA-gyrase ATP-binding site using the computational drug design platform SkelGen. We have generated an exhaustive number of structural possibilities, which were subsequently filtered for site complementarity and synthetic tractability. A number of known active fragments are found, but most of the species created are potentially novel and could be valuable for further elaboration and development into lead-like structures.

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