Multiple fragment docking and linking in primary and secondary pockets of dopamine receptors

ACS Med Chem Lett. 2014 Jul 10;5(9):1010-4. doi: 10.1021/ml500201u. eCollection 2014 Sep 11.


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.

Keywords: Fragment docking; G protein-coupled receptors; dopamine receptors; fragment linking; selective antagonists.