A computational investigation to find Potential 5-HT 2C receptor drugs to treat Schizophrenia by ADMET Profile Analysis, Molecular Docking, DFT, Network Pharmacology and Molecular Dynamic Simulation

Background: Schizophrenia is a heterogeneous psychiatric disorder that is poorly treated with current therapies. Schizophrenia affects approximately 24 million people or 1 in 300 people (0.32%) worldwide. This rate is approximately 1 in 222 people (0.45%) among adults. Hence, this research is focused on 5-hydroxytryptamine (5-HT 2C), which has a significant effect in the modulation of monoaminergic transmission, motor behavior, and endocrine secretion, that plays a significant role in the series of events that lead to Schizophrenia.

Methodology: Using a computational ligand-based method, the molecular chemical characteristics of 5-HT 2C inhibition were determined. Potential inhibitors such as Ephemeranthoquinone and Actinodaphnine were investigated from Arundina graminifolia (Orchidaceae) and Litsea polyantha (Lauraceae). In this study, DFT 6-31g(d,p) basis set, ADMET, and the Gaussian 16 software package were utilized to compute the physical, chemical, spectral, and thermodynamic properties of specific ligands. The interaction between ligands and proteins was examined with PyRx, Chimera 1.15. Molecular orbital studies were used to calculate the softness and binding characteristics whereas network pharmacology study examined the interaction of protein and ligands. Additionally, pharmacokinetics was assessed using renowned web tools such as admetSAR, ProTox-3.0 for predicting toxicity. Moreover, 100 nanoseconds molecular dynamics simulation analysis using Desmond to ensure the stability of these two compounds.

Results: Based on computational research, drug binding site evaluation, docking score, optimization, and molecular dynamic simulation results Ephemeranthoquinone and Actinodaphnine are the most selective 5-HT 2C inhibitors.

Conclusion: These compounds are required to be studied further to develop a useful 5-HT 2C inhibitor for the treatment of schizophrenia.