Multiple Fragment Docking and Linking in Primary and Secondary Pockets of Dopamine Receptors
Gyorgy Keseru,
Director General,
Hungarian Academy of Sciences
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 subnanomolar potency on D3 receptors and 9, 39 and 55-fold selectivity over D2 that has been assessed on a structural basis.
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