Virtual screening, molecular docking and dynamics simulation studies to identify potential agonists of orphan receptor GPR78 targeting CNS disorders.

G protein-coupled receptors (GPCRs) are important targets in drug discovery because of their roles in physiological and pathological processes. Orphan GPCRs are GPCR proteins for which endogenous ligands have not yet been identified and they present interesting avenues for therapeutic intervention. This study focuses on GPR78, an orphan GPCR that is expressed in the central nervous system and linked to neurological disorders. GPR78 has no reported crystal structure and there is limited research. In this study, we have predicted the three dimensional model of GPR78 and its probable binding pocket. Structure-based virtual screening was carried out using the ChemDiv and Enamine REAL databases, followed by induced-fit docking studies to identify potential lead compounds with favorable interactions. These lead compounds were then embedded into a POPC lipid bilayer for a 200 ns molecular dynamics simulation. Free energy landscapes and MM-PBSA analyses were performed to assess the binding energies and conformational dynamics. The results highlight the dynamic nature of GPR78 in the presence of lead compounds and show favorable binding interactions. This study aims to predict a reliable three dimensional model of GPR78 and identify novel lead compounds through a comprehensive in silico approach. The identification of these potential GPR78 agonists represents a significant step in the development of new therapeutics for neurological disorders, highlighting the therapeutic potential of orphan GPR78 in CNS disorders.

Discovery of potential TAAR1 agonist targeting neurological and psychiatric disorders: An in silico approach.

Trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptor which is primarily expressed in the brain. It is activated by trace amines which play a role in regulating neurotransmitters like dopamine, serotonin and norepinephrine. TAAR1 agonists have potential applications in the treatment of neurological and psychiatric disorders, especially schizophrenia. In this study, we have used a structure-based virtual screening approach to identify potential TAAR1 agonist(s). We have modelled the structure of TAAR1 and predicted the binding pocket. Further, molecular docking of a few well-known antipsychotic drugs was carried out with TAAR1 model, which showed key interactions with the binding pocket. From screening a library of 5 million compounds from the Enamine REAL Database using structure-based virtual screening method, we shortlisted 12 compounds which showed good docking score, glide energy and interactions with the key residues. One lead compound (Z31378290) was finally selected. The lead compound showed promising binding affinity and stable interactions with TAAR1 during molecular dynamics simulations and demonstrated better van der Waals and binding energy than the known agonist, ulotaront. Our findings suggest that the lead compound may serve as a potential TAAR1 agonist, offering a promising avenue for the development of new therapies for neurological and psychiatric disorders.

Orphan receptor GPR88 as a potential therapeutic target for CNS disorders - an in silico approach.

The G-protein-coupled receptors are a part of the largest and most physiologically relevant family of membrane proteins. One-third of the medications, now on the market, target the GPCR receptor family, which is one of the most important therapeutic targets for many disorders. In the reported work, we have focussed on orphan GPR88 receptor which is a part of the GPCR protein family and a potential target for central nervous system disorders. GPR88 is known to show the highest expression in the striatum, which is a key region in motor control and cognitive functions. Recent studies have reported that GPR88 is activated by two agonists, 2-PCCA and RTI-13951-33. In this study, we have predicted the three-dimensional protein structure for the orphan GPR88 using the homology modeling approach. We then used shape-based screening techniques based on known agonists and structure-based virtual screening methods employing docking to uncover novel GPR88 ligands. The screened GPR88-ligand complexes were further subjected to molecular dynamics simulation studies. The selected ligands could fasten the development of novel treatments for the vast list of movement and central nervous system disorders.Communicated by Ramaswamy H. Sarma.

Design and synthesis of heterocyclic azole based bioactive compounds: Molecular structures, quantum simulation, and mechanistic studies through docking as multi-target inhibitors of SARS-CoV-2 and cytotoxicity.

Two heterocyclic azole compounds, 3-(2,3-dihydrobenzo[d]thiazol-2-yl)-4H-chromen-4-one (SVS1) and 5-(1H-indol-3-yl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (SVS2) were obtained unexpectedly from 2-aminothiophenol and 4-oxo-4H-chromene-3-carbaldehyde (for SVS1), and (E)-2-((1H-indol-3-yl)methylene)-N-methylhydrazine-1-carbothioamide in the presence of anhydrous FeCl3 (for SVS2), respectively. The compounds were well characterized by analytical and spectroscopic tools. The molecular structures of both the compounds were determined by single crystal X-ray diffraction (XRD) study. The results obtained from density functional theory (DFT) study revealed the molecular geometry and electron distribution of the compounds, which were correlated well with the three-dimensional structures obtained from the single crystal XRD. DMol3 was used to calculate quantum chemical parameters [chemical potential (µ), global hardness (η), global softness (σ), absolute electronegativity (χ) and electrophilicity index (ω)] of SVS1 and SVS2. Molecular docking study was performed to elucidate the binding ability of SVS1 and SVS2 with SARS-CoV-2 main protease and human angiotensin-converting enzyme-2 (ACE-2) molecular targets. Interestingly, the binding efficiency of the compounds with the molecular targets was comparable with that of remdesivir (SARS-CoV-2), chloroquine and hydroxychloroquine. SVS1 showed better docking energy than SVS2. The molecular docking study was complemented by molecular dynamics simulation study of SARS-CoV-2 main protease-SVS1 complex, which further exemplified the binding ability of SVS1 with the target. In addition, SVS1, SVS2 and cisplatin were assessed for their cytotoxicity against a panel of three human cancer cells such as HepG-2 (hepatic carcinoma), T24 (bladder) and EA.hy926 (endothelial), as well as Vero (kidney epithelial cells extracted from an African green monkey) normal cells using MTT assay. The results showed that SVS2 has significant cytotoxicity against HepG-2 and EA.hy926 cells with the IC50 values of 33.8 µM (IC50 = 49.9 µM-cisplatin and 8.6 µM-doxorubicin) and 29.2 (IC50 = 26.6 µM-cisplatin and 3.8 µM-doxorubicin), respectively.