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J Chem Inf Model. 2017 Dec 26;57(12):3104-3123. doi: 10.1021/acs.jcim.7b00528. Epub 2017 Nov 28.

Demystifying P2Y1 Receptor Ligand Recognition through Docking and Molecular Dynamics Analyses.

Author information

1
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892, United States.

Abstract

We performed a molecular modeling analysis of 100 nucleotide-like bisphosphates and 46 non-nucleotide arylurea derivatives previously reported as P2Y1R binders using the recently solved hP2Y1R structures. We initially docked the compounds at the X-ray structures and identified the binding modes of representative compounds highlighting key patterns in the structure-activity relationship (SAR). We subsequently subjected receptor complexes with selected key agonists (2MeSADP and MRS2268) and antagonists (MRS2500 and BPTU) to membrane molecular dynamics (MD) simulations (at least 200 ns run in triplicate, simulation time 0.6-1.6 μs per ligand system) while considering alternative protonation states of nucleotides. Comparing the temporal evolution of the ligand-protein interaction patterns with available site-directed mutagenesis (SDM) data and P2Y1R apo state simulation provided further SAR insights and suggested reasonable explanations for loss/gain of binding affinity as well as the most relevant charged species for nucleotide ligands. The MD analysis also predicted local conformational changes required for the receptor inactive state to accommodate nucleotide agonists.

PMID:
29182323
PMCID:
PMC5953180
DOI:
10.1021/acs.jcim.7b00528
[Indexed for MEDLINE]
Free PMC Article

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