Computational approaches for the design of novel dopamine D2 and serotonin 5-HT2A receptor dual antagonist towards schizophrenia

Abstract

Piperidine and piperazine derivatives exhibit a diverse range of biological applications, including antipsychotic activity. In this study, a dataset of molecules containing piperidine, piperazine moieties that possess serotonin 5-HT 2A and dopamine D 2 inhibitory activity have been chosen for Pharmacophore modeling, Quantitative Structure–Activity (3D-QSAR) Relationship, Molecular docking, and ADME studies. The pharmacophoric hypothesis was found to be AAHPRRR_1 having seven features as one H-bond acceptor (A), one hydrophobic (H), one positive ion acceptor (P), and three aromatic rings (R), with survival score = 6.465 and AUC = 0.92. Based on the best hypothesis, the ZINC-Data base was virtually screened to find out the lead molecules. 3D-QSAR model, including internal and external validation showed comparative molecular field analysis (CoMFA) against 5HT 2A ( q 2 = 0.552, R 2 = 0.889, and r 2 poured. = 0.653 and number of component 5) and comparative molecular similarity indices analysis (CoMSIA) ( q 2 = 0.599, R 2 = 0.893, and r 2 pred. = 0.617), for D 2 (CoMFA, q 2 = 0.577, R 2 = 0.863, and r 2 pred. = 0.598) (CoMSIA, q 2 = 0.532, R 2 = 0.82) all results exhibited better productivity and significant statistical reliability of the model. The docking study was carried out on the crystal structure of 5-HT 2A having PDB ID; 6A93 and D 2 receptor having PDB ID; 6CM4. The screened compound ZINC74289318 possess a higher docking score − 10.744 and − 11.388 than co-crystallized ligand docking score − 8.840 and − 10.06 against 5-HT 2A and D 2 receptor respectively. Further, ZINC74289318 was screened for all drug-likeness parameters and no showed violation of the Lipinski rule of five. Also, it was found to possess good bioavailability of 0.55 with synthetic accessibility of 4.42 which is greater than risperidone.

Unravelling the Molecular Mechanisms of a Quercetin Nanocrystal for Treating Potential Parkinson’s Disease in a Rotenone Model: Supporting Evidence of Network Pharmacology and In Silico Data Analysis

“…Akash Rathore et al's study also identified the critical structural amino acid residues of the D2 receptor as Asp114, Trp386, and Phe390. Interestingly, QUE interacted with two vital amino acids, Asp114 via electrostatic interactions and Trp386 via hydrophobic interactions, while the standard L-dopa interacted only with Asp114 via both hydrogen and electrostatic bond interactions [62]. Therefore, the top two ranked targets, DRD2 and DRD4, were evaluated using in vivo studies to determine the dopamine levels.…”

Towards Novel Potential Molecular Targets for Antidepressant and Antipsychotic Pharmacotherapies

“…Some studies also combine docking with (Q)SAR methods, e.g., identifying monoamine neurotransmitters reuptake inhibitors as antidepressants [204] or a selective positive allosteric modulation of α1containing GABA-A receptors [196]. The use of only QSAR models, albeit less common than docking studies, has linked antidepressant effects to MAO A [205], serotonin 5-HT2A receptor [206] and norepinephrine/dopamine reuptake activity [207], and antipsychotic effects -to 5-HT6 [208], D2, 5-HT2A [209] and sigma-2 receptors [210].…”

Antidepressant and Pharmacokinetic Evaluation of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) of Escitalopram

“…The activation of the 5HT2A receptor results in decreased postjunctional 5HT1A signalling in the forebrain which leads to the onset of depression [24]. The key amino acid residues ILE163, PHE332 and TRP336 were found to be a prerequisite for both receptor activation and biological activity [25]. The 5HT2A receptor antagonist promotes the activity of other serotonin receptors (5HT1A) that limit neuronal ring by potassium channel opening, which is signi cant in the treatment of depressive disorders [26].…”