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Homology modeling, molecular dynamic simulation, and docking based binding site analysis of human dopamine (D4) receptor

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Abstract

Human dopamine D4 receptor is a GPCR target in the treatment of neurological and psychiatric conditions such as schizophrenia and Parkinson’s disease. The X-ray structure of this receptor has not been resolved so far. Therefore, a proper 3D structure of D4 could provide a good tool in order to design novel ligands against this target. In this study, homology modeling studies were performed to obtain a reasonable structure of the receptor using known templates. The obtained model was subjected to molecular dynamic simulation within a DPPC membrane system. Some structural features of the receptor such as a conserved disulfide bridge and ionic lock were considered in the modeling experiments. The resulted trajectories of simulation were clustered based on the root mean square deviation of the backbone. Some known ligands and decoys were accordingly docked into the representative frames of each cluster. The best final model was finally selected based on its ability to discriminate between active ligands and inactive decoys (ROC = 0.839). The presented model of human D4 receptor could be a promising starting point in future studies of drug design for the described target.

Superposition of human D4 model with the crystal structure of D3 at TM regions

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Acknowledgments

The support from the Research Council at Shiraz University of Medical Sciences is acknowledged. The authors would like to thank Nazanin Bagherzadeh for her kind contribution in language editing of the manuscript. This work is a PharmD dissertation report, performed by Minasadat Khoddami, student of pharmacy at Shahid Sadoughi University of Medical Sciences.

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Authors and Affiliations

  1. Department of Medicinal Chemistry, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

    Minasadat Khoddami, Hamid Nadri & Alireza Moradi

  2. Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran

    Amirhossein Sakhteman

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  1. Minasadat Khoddami
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  2. Hamid Nadri
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Correspondence to Amirhossein Sakhteman.

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Khoddami, M., Nadri, H., Moradi, A. et al. Homology modeling, molecular dynamic simulation, and docking based binding site analysis of human dopamine (D4) receptor. J Mol Model 21, 36 (2015). https://doi.org/10.1007/s00894-015-2579-3

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