Homology modeling of the human 5-HT1A, 5-HT2A, D1, and D2 receptors: model refinement with molecular dynamics simulations and docking evaluation

Abstract

5-HT(1A) serotonin and D1 dopamine receptor agonists have been postulated to be able to improve negative and cognitive impairment symptoms of schizophrenia, while partial agonists and antagonists of the D2 and 5-HT(2A) receptors have been reported to be effective in reducing positive symptoms. There is therefore a need for well-defined homology models for the design of more selective antipsychotic agents, since no three-dimensional (3D) crystal structures of these receptors are currently available. In this study, homology models were built based on the high-resolution crystal structure of the β(2)-adrenergic receptor (2RH1) and further refined via molecular dynamics simulations in a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer system with the GROMOS96 53A6 united atom force field. Docking evaluations with representative agonists and antagonists using AutoDock 4.2 revealed binding modes in agreement with experimentally determined site-directed mutagenesis data and significant correlations between the computed and experimental pK (i) values. The models are also able to distinguish between antipsychotic agents with different selectivities and binding affinities for the four receptors, as well as to differentiate active compounds from decoys. Hence, these human 5-HT(1A), 5-HT(2A), D1 and D2 receptor homology models are capable of predicting the activities of novel ligands, and can be used as 3D templates for antipsychotic drug design and discovery.

Computational and Experimental Analysis of the Transmembrane Domain 4/5 Dimerization Interface of the Serotonin 5-HT1A Receptor

“…This is in agreement with our structural model, in which both Trp175 4.64 and Tyr198 5.41 point to the dimerization interface and not into the binding pocket. Arg176 4.65 does point into the upper part of the TM core but it is not part of the binding site as defined either by (Yap et al, 2012) or by analogy to dopamine D 3 receptor binding site (Chien et al, 2010) (see Supplemental Fig. 1).…”

“…We have defined the putative binding site of the 5-HT 1A in two ways: 1) by using the ligand-docking results (Yap et al, 2012), which listed the residues that are in direct contact with serotonin (Ser199 5.42 , Thr200 5.43 , and Asp116 3.32 ) and pinolol (Asp116 3.32 , Ile113 3.29 , Lys191 5.34 , and Asn386 7.39 ); 2) by using analogy to dopamine D 3 receptor (D3) X-ray structure. For this purpose, we superposed the 5-HT 1A model The table show for each model the server that was used for preparing it.…”

Synthesis, antibacterial, and antifungal activities of new drimane sesquiterpenoids with azaheterocyclic units

“…Homology model of dopamine D 2 receptor in inactive conformation was also built by Malo et al (2012), Yap et al (2012), and Duan et al (2015) using β 2 adrenergic receptor as a template. Sukalovic et al (2013) used D 3 receptor as a template while Kołaczkowski et al (2013) compared models built on both templates.…”

Prospecting for Novel Plant-Derived Molecules of Rauvolfia serpentina as Inhibitors of Aldose Reductase, a Potent Drug Target for Diabetes and Its Complications

“…These energy rankings, along with the criterion of interaction with critical residues, were used to evaluate the ability of protocol to preferentially select the actives from decoys. Application of this procedure has been reported to improve the performance of ROC analysis [65].…”