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

Vass, Márton and Ágai-Csongor, Éva and Horti, Ferenc and Keserű, György Miklós (2014) Multiple Fragment Docking and Linking in Primary and Secondary Pockets of Dopamine Receptors. ACS MEDICINAL CHEMISTRY LETTERS, 5 (9). pp. 1010-1014. ISSN 1948-5875

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Abstract

A sequential docking methodology was applied to computationally predict starting points for fragment linking using the human dopamine D-3 receptor crystal structure and a human dopamine D-2 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 D-3 and the subtype selectivity of the compounds was assessed on a structural basis.

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