BMERC Seminar: Exploiting secondary binding pockets in aminergic GPCRs
When: Thursday, June 22, 12 pm
Where: ENG room 203, 44 Cummington Street
Title: Exploiting secondary binding pockets in aminergic GPCRs
Speaker: Dr. Gyorgy Keseru, Medicinal Chemistry Research Group, Hungarian Academy of Science, Budapest, Hungary
Abstract: Fragment based drug discovery (FBDD) employs growing and linking strategies for optimization. Structural information on G-protein coupled receptors (GPCRs) made FBDD available on this class of targets, however, most reported programs applied a growing strategy starting from orthosteric fragment binders. We developed a sequential docking methodology to support the identification of primary (orthosteric) and secondary site binders and linking of these fragment hits. Predicting the binding mode of multiple fragments bound to a single target we assessed the sampling and scoring accuracy for the first and second site binders in self- and cross-docking situations. The prospective validation of this approach was performed on dopamine receptors 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. A set of linked compounds created from the best scored primary and secondary site binders were synthesized from which we identified a number of D3 favoring compounds including one with 200-fold D3 selectivity. The structural assessment of the subtype selectivity of the compounds allowed us to identify further compounds with high affinity and improved selectivity. Now we are extending the methodology to further aminergic GPCR targets.