Molecular modeling and molecular dynamics simulations were performed in the present study to examine the modes of dopamine binding with human and Drosophila dopamine transporters (hDAT and dDAT). The computational data revealed flipped binding orientations of dopamine in hDAT and dDAT due to the major differences in three key residues (S149, G153, and A423 of hDAT vs A117, D121, and S422 of dDAT) in the binding pocket. These three residues dictate the binding orientation of dopamine in the binding pocket, as the aromatic ring of dopamine tends to take an orientation with both the para- and meta-hydroxyl groups being close to polar residues and away from nonpolar residues of the protein. The flipped binding orientations of dopamine in hDAT and dDAT clearly demonstrate a generally valuable insight concerning how the species difference could drastically affect the protein-ligand binding modes, demonstrating that the species difference, which is a factor rarely considered in early drug design stage, must be accounted for throughout the ligand/drug design and discovery processes in general.
|Number of pages||6|
|Journal||ACS Chemical Neuroscience|
|State||Published - Jun 20 2018|
Bibliographical noteFunding Information:
*Phone: 859-323-3943. Fax: 859-257-7585. E-mail: zhan@uky. edu. ORCID Chang-Guo Zhan: 0000-0002-4128-7269 Author Contributions Y.Y. performed the modeling studies and drafted the manuscript. C.-G.Z. designed the research project with contribution from J.Z., and C.-G.Z. finalized the manuscript. Funding This work was supported in part by the NIH (Grants R01 DA035714, R01 DA035552, R01 DA032910, and R01 DA025100) and the NSF (Grant CHE-1111761). Notes The authors declare no competing financial interest.
© 2018 American Chemical Society.
- Protein-ligand binding
- dopamine system
- molecular dynamics
- molecular modeling
- species difference
ASJC Scopus subject areas
- Cognitive Neuroscience
- Cell Biology