Plenary Lecture 8

Title: Exploiting secondary binding pockets in aminergic GPCRs.

Professor György Miklós Keserü

Hungarian Academy of Sciences, Hungary

Lecture Summary:
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 working on the extension of this methodology to other aminergic GPCR targets including adrenergic, histaminergic, and serotoninergic receptors.


Acknowledgments: Ádám Kelemen (RCNS Hungary), Krzysztof Rataj and Andrzej Bojarski (IF, PAS, Krakkow, Poland), Márton Vass, Chris de Graaf, Iwan de Esch, and Rob Leurs (VU Amsterdam, The Netherlands), Peter Kolb (Uni. Marburg, Germany) are the main collaborators of this project. All the collaborators are participating in the CM1207 GLISTEN COST Action supported by the European Comission.


References: Vass, M., Keserű, G.M. MedChemComm 2013, 4, 510-514.

Vass, M., Ágai-Csongor, É., Horti, F., Keserű, G.M. ACS Med. Chem. Lett. 2014, 5, 1010-4.