sCMBI and Organon excel in global GPCR modeling competition


A team of scientists from the Centre for Molecular and Biomolecular Informatics (CMBI, Radboud University Nijmegen Medical Centre) and Department of Molecular Design and Informatics (MSD/Organon) recently participated in a prestigious world-wide challenge in predicting the binding orientation and interactions of small molecule inhibitors to two different G protein-coupled receptors (GPCRs).

In a joint effort Marijn Sanders, Bas Vroling, Jan Klomp, Jacob de Vlieg and Sander Nabuurs used computer simulations to predict the three-dimensional structure of these complexes, prior to the release of the experimentally determined crystal structures.

 Excellent results were obtained for both the dopamine D3 receptor (DRD3), a target for drugs which treat schizophrenia, drug addiction, and Parkinson's disease, as the CXCR4 receptor, involved in HIV infection and cancer. For the DRD3 receptor, out of over a hundred models entered by 32 internationally renowned groups, all five submitted predictions ranked in the top 10 best models with the best model ranking second. Not only was the CMBI/MSD team the only with multiple models in the top 10, they were also the only team to succeed in correctly ranking the submitted predictions. The group's most accurate prediction for CXCR4 was ranked 14th out of the in total 103 submitted models. Remarkably, the best prediction for this target was generated by another Dutch team: the Medicinal Chemistry group of VU University Amsterdam. Both also collaborate in the Dutch Top Institute Pharma GPCR forum.

 To generate these successful predictions, the joint CMBI/MSD team utilized in-house developed modeling approaches, combining the protein-based pharmacophore modeling program Snooker (developed by Marijn Sanders and Jan Klomp as part of the Dutch Top Institute Pharma GPCR forum) with the flexible docking program Fleksy (an NWO-Veni project of Sander Nabuurs).

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