Molecular modeling and docking studies of human 5-hydroxytryptamine 2A (5-HT2A) receptor for the identification of hotspots for ligand binding

Abstract

The serotonergic system has been implicated in emotional and cognitive function. In particular, 5-HT(2A) (5-hydroxytrytamine receptor 2A) is attributed to a number of disorders like schizophrenia, depression, eating disorders and anxiety. 5-HT(2A), being a GPCR (G-protein coupled receptor), is important in the pharmaceutical industry as a proven target for these disorders. Despite their extensive clinical importance, the structural studies of this protein is lacking due to difficulties in determining its crystal structure. We have performed sequence analysis and molecular modeling of 5-HT(2A) that has revealed a set of conserved residues and motifs considered to play an important role in maintaining structural integrity and function of the receptor. The analysis also revealed a set of residues specific to the receptor which distinguishes them from other members of the subclass and their orthologs. Further, starting from the model structure of human 5-HT(2A) receptor, docking studies were attempted to envisage how it might interact with eight of its ligands (such as serotonin, dopamine, DOI, LSD, haloperidol, ketanserin, risperidone and clozapine). The binding studies of dopamine to 5-HT(2A) receptor can bring up better understanding in the etiology of a number of neurological disorders involving both these two receptors. Our sequence analysis and study of interactions of this receptor with other ligands reveal additional residue hotspots such as Asn 363 and Tyr 370. The function of these residues can be further analyzed by rational design of site-directed mutagenesis. Two distinct binding sites are identified which could play important roles in ligand binding and signaling.

Affinity of aporphines for the human 5-HT2A receptor: Insights from homology modeling and molecular docking studies

“…The results obtained in our work suggest that nantenine and the C1 alkyl analogs bind in the site bordered by TM3-TM6 and utilize the key Asp155 interaction but are oriented differently as shown diagramatically in Figure 10. Based on the residues that are used to establish key interaction to the ligands, the analogs also appear to bind in a manner different from that reported for other known antagonists such as ketanserin and haloperidol which supports the assertion that the structure of the ligand impacts its orientation and preference for residues in certain helices that are utilized for binding 48. Indeed it is clear that the binding pocket is tolerant of a variety of structural classes of ligands which may adopt different orientations between classes as well as within a given class as seen here with nantenine and its analogs.…”

“…Sowdhamini et al recently reported the construction of a homology model of the human 5-HT 2A receptor based on a human β2 adrenoceptor template 48. In this study they docked a number of known 5-HT 2A antagonists and inverse agonists (ketanserin, haloperidol, clozapine and risperidone) using the program Autodock 4.0.…”

Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro

“…For example, some hallucinogens bind to and stimulate specific 5-HT receptors (Nichols et al, 2002, Rabin et al, 2002; Kanagarajadurai et al, 2009; for review see Halberstadt and Geyer, 2011) and LSD interacts with specific dopaminergic and noradrenergic receptors (Minuzzi and Cumming, 2010). In contrast, many first generation antipsychotic agents block dopamine D 2 receptors, and second generation antipsychotic drugs block D 2 and (or) 5-HT 2 receptors (Miyake et al, 2012).…”

Flow and Microwave Induced Pellizzari Reactions: Synthesis of Heterocyclic Analogues of the Benzoxazepine Antipsychotic Agents Loxapine and JL-13

“…Given literature reports citing the importance of both basic amino functionality and a hydrophobic substituent (e.g., chloroaryl group) for optimal receptor binding [15,16], a more elaborate substrate 5 was also prepared from hydrazide 4 (readily available from m-chloro-o-toluic acid), leading to the target compound in 87% yield (see Scheme 3). Given the impressive results with the MW Pellizzari reaction, a second family of analogues were prepared which contain the chloroaryl functionality on the parent tricyclic ring system.…”

“…[3,2- 15.26 mmol), and N,N-dimethylaniline (2.57 mL, 20.32 mmol) in dry toluene (10 mL) was heated at reflux for 2 h. The reaction mixture was cooled to ambient temperature and excess solvents were evaporated under reduced pressure. The resulting residue was dissolved in THF (20 ml) and Na 2 CO 3 (30 mL of 2 M solution) and heated at 80 ∘ C for 1 h. The reaction mixture was cooled to ambient temperature and THF was removed under reduced pressure.…”