Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs

Ferruz, Noelia; Doerr, Stefan; Vanase-Frawley, Michelle A.; Zou, Yaozhong; Chen, Xiaomin; Marr, Eric S.; Nelson, Robin T.; Kormos, Bethany L.; Wager, Travis T.; Hou, Xinjun; Villalobos, Anabella; Sciabola, Simone; De Fabritiis, Gianni

doi:10.1038/s41598-018-19345-7

Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs

Journal Article · Tue Jan 16 23:00:00 EST 2018 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-018-19345-7· OSTI ID:1440593

Ferruz, Noelia ^[1]; Doerr, Stefan ^[1]; Vanase-Frawley, Michelle A. ^[2]; Zou, Yaozhong ^[2]; Chen, Xiaomin ^[2]; Marr, Eric S. ^[2]; Nelson, Robin T. ^[2]; Kormos, Bethany L. ^[3]; Wager, Travis T. ^[3]; Hou, Xinjun ^[3]; Villalobos, Anabella ^[3]; Sciabola, Simone ^[3]; De Fabritiis, Gianni ^[4]

Univ. Pompeu Fabra, Barcelona (Spain); Acellera, Barcelona (Spain)
Pfizer Worldwide Research and Development, Groton, CT (United States)
Pfizer Worldwide Research and Development, Cambridge, MA (United States)
Univ. Pompeu Fabra, Barcelona (Spain); Acellera, Barcelona (Spain); Inst. Catalana de Recerca i Estudis Avançats (ICREA), Barcelona (Spain)

The recent increase in the number of X-ray crystal structures of G-protein coupled receptors (GPCRs) has been enabling for structure-based drug design (SBDD) efforts. These structures have revealed that GPCRs are highly dynamic macromolecules whose function is dependent on their intrinsic flexibility. Unfortunately, the use of static structures to understand ligand binding can potentially be misleading, especially in systems with an inherently high degree of conformational flexibility. Here, we show that docking a set of dopamine D3 receptor compounds into the existing eticlopride-bound dopamine D3 receptor (D3R) X-ray crystal structure resulted in poses that were not consistent with results obtained from site-directed mutagenesis experiments. We overcame the limitations of static docking by using large-scale high-throughput molecular dynamics (MD) simulations and Markov state models (MSMs) to determine an alternative pose consistent with the mutation data. The new pose maintains critical interactions observed in the D3R/eticlopride X-ray crystal structure and suggests that a cryptic pocket forms due to the shift of a highly conserved residue, F^6.52. Our study highlights the importance of GPCR dynamics to understand ligand binding and provides new opportunities for drug discovery.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: MINECO; FEDER

OSTI ID:: 1440593

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Journal Issue: 1 Vol. 8; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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