Paper Info
Title
Ligand Binding Pathways of Clozapine and Haloperidol in the Dopamine D2 and D3 Receptors.
Abstract
The binding of a small molecule ligand to its protein target is most often characterized by binding affinity and is typically viewed as an on/off switch. The more complex reality is that binding involves the ligand passing through a series of intermediate states between the solution phase and the fully bound pose. We have performed a set of 29 unbiased molecular dynamics simulations to model the binding pathways of the dopamine receptor antagonists clozapine and haloperidol binding to the D-2 and D-3 dopamine receptors. Through these simulations we have captured the binding pathways of clozapine and haloperidol from the extracellular vestibule to the orthosteric binding site and thereby, we also predict the bound pose of each ligand. These are the first long time scale simulations of haloperidol or clozapine binding to dopamine receptors. From these simulations, we have identified several important stages in the binding pathway, including the involvement of Tyr7.35 in a "handover" mechanism that transfers the ligand between the extracellular vestibule and Asp3.32. We have also performed interaction and cluster analyses to determine differences in binding pathways between the D-2 and D-3 receptors and identified metastable states that may be of use in drug design.
Year
DOI
Venue
2016
10.1021/acs.jcim.5b00457
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Field
DocType
Volume
Plasma protein binding,Dopamine receptor,Binding site,Ligand,Biophysics,Ligand (biochemistry),Combinatorial chemistry,Chemistry,Receptor,Dopamine receptor D2,Haloperidol,Stereochemistry
Journal
56
Issue
ISSN
Citations 
2
1549-9596
0
PageRank 
References 
Authors
0.34
13
4
Name
Order
Citations
PageRank
Trayder Thomas130.86
Yu Fang200.34
Elizabeth Yuriev3203.70
David K. Chalmers4163.26