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

• Published in: Journal of molecular modeling 2015-02, Vol.21 (2), p.36-36, Article 36
• Main Authors: Khoddami, Minasadat, Nadri, Hamid, Moradi, Alireza, Sakhteman, Amirhossein
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Binding Sites; Characterization and Evaluation of Materials; Chemistry; Chemistry and Materials Science; Computer Appl. in Life Sciences; Computer Applications in Chemistry; Humans; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Medicine; Molecular Sequence Data; Original Paper; Protein Binding; Protein Interaction Domains and Motifs; Quantitative Structure-Activity Relationship; Receptors, Dopamine D4 - chemistry; ROC Curve; Sequence Homology, Amino Acid; Theoretical and Computational Chemistry
• ISSN: 1610-2940; 0948-5023
• DOI: 10.1007/s00894-015-2579-3

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