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Multiple Fragment Docking and Linking in Primary and Secondary Pockets of Dopamine Receptors

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† Gedeon Richter Plc, Gyömrői út 19-21, H-1103 Budapest, Hungary
‡ Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary
*(G.M.K.) Tel: +36-1- 382-6900. Fax: +36-1- 382-6297. E-mail: [email protected]
Cite this: ACS Med. Chem. Lett. 2014, 5, 9, 1010–1014
Publication Date (Web):July 10, 2014
https://doi.org/10.1021/ml500201u
Copyright © 2014 American Chemical Society
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    Abstract

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    A sequential docking methodology was applied to computationally predict starting points for fragment linking using the human dopamine D3 receptor crystal structure and a human dopamine D2 receptor homology model. Two focused fragment libraries were docked in the primary and secondary binding sites, and best fragment combinations were enumerated. Similar top scoring fragments were found for the primary site, while secondary site fragments were predicted to convey selectivity. Three linked compounds were synthesized that had 9-, 39-, and 55-fold selectivity in favor of D3 and the subtype selectivity of the compounds was assessed on a structural basis.

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    General formulas of the focused fragment libraries; synthetic and experimental details. This material is available free of charge via the Internet at http://pubs.acs.org.

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