GPUgrid Science non-stop: another paper, another badge

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#1 GPUgrid Science non-stop: another paper, another badge

Post by Newshound »


...and here's another badge for another publication issued in 2018, Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs. This one is also on Sci. Rep., open access.

Here, the authors used Gpugrid-based simulations to reconcile experimental results on Dopamine D3 receptor antagonists with their molecular structures. They used the large-scale high-throughput molecular dynamics with Markov state models (MSMs) to determine an alternative and possibly elusive pose ("cryptic") consistent with the mutation data.

Thanks to every contributor!


Noelia Ferruz, Stefan Doerr, Michelle A. Vanase-Frawley, Yaozhong Zou, Xiaomin Chen, Eric S. Marr, Robin T. Nelson, Bethany L. Kormos, Travis T. Wager, Xinjun Hou, Anabella Villalobos, Simone Sciabola & Gianni De Fabritiis
Dopamine D3 receptor antagonist reveals a cryptic pocket in aminergic GPCRs
Scientific Reportsvolume 8, Article number: 897 (2018)

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, F6.52. Our study highlights the importance of GPCR dynamics to understand ligand binding and provides new opportunities for drug discovery.



Source: http://www.gpugrid.net/forum_thread.php?id=4959
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