Computational Approaches in Evaluating the 5-HT Subtype Receptor Mechanism of Action for Developing Novel Chemical Entities

The G-protein coupled receptor GPCR family is the most numerous and diversified set of membrane receptors linked with various neurological disorders like Epilepsy, Alzheimer's disease, Fronto-temporal dementia, Vascular dementia, Parkinson's disease, and Huntington's disease. They provide messages to the cell by interacting with various ligands, which include hormones, neurotransmitters, and photons. They are the focus of roughly one-third of the medications on the market today. Similarly, the subtype of the serotonin receptor, 5-hydroxytryptamine 2B (5-HT2B), belongs to the G-protein receptor (GPCR) class-A family and is a sensitive class prone to deactivation and activation. There has been an increasing interest in the structural geometry of the receptor upon ligand binding to the allosteric site. The cavities at the receptor-lipid interface are an unusual allosteric binding region that presents numerous issues concerning ligand interactions and stability, binding site conformation, and how the lipid molecules alter all these molecular modeling mechanisms provide an insight into the docking and binding of drug and structural variations. For instance, ligand recognition in the neuronal adenosine receptor type 2A (hA2AR), a GPCR related to various neurodegenerative disorders, was investigated for its affinity against an inhibitor in a solvated neuronal-like membrane in metadynamics. The study provided a factual description of atomic interactions between the ligand and the receptor. It was supported by in vitro binding affinity studies for highlighting the importance of membrane lipids and protein extracellular loop regions, thus, providing valuable input for ligand design and targeting GPCR. Since 5HT is essential as a target for various pharmaceutical and recreational drugs, studies are gaining pace regarding its seven subtypes. In research, general molecular design is carried out, including homology modeling, docking, dynamics, and a hallucinogen-specific chemogenomics database for pharmacological analysis of small molecules and their potential targets. The analogs of piperidine and piperazine moieties were investigated against the 5HT2A receptor via pharmacophore modeling, 3D-Quantitative Structure-Activity Relationship (3D-QSAR), Molecular docking, and Absorption Distribution Metabolism Excretion (ADME) studies. With the onset of multiscale molecular modeling, it is now possible to apply multiple levels of theory to a system of interest, such as assigning chemically relevant regions to high quantum mechanics (QM) theory while treating the rest of the system with a classical force field (molecular mechanics (MM) potential). Several groups have explored the atomic level of interaction between the ligand and the allosteric site via molecular docking and dynamics simulations, followed by quantum chemical calculations to achieve specific results and strengthen the analysis. Quantum Mechanics/Molecular Mechanics (QM/MM) is employed by considering conformational plasticity to identify the critical binding site residues responsible for modifying GPCR function. By this path, the geometry of the receptor is analyzed either by fixing its position w.r.t. to the ligand or by choosing a bound ligand. Finally, structure-based drug design (SBDD) methodologies will be more efficient. Density Functional Theory (DFT) calculations reveal the stabilization of the molecular structure to depict the interactions. Various study groups also practice Fragment-based lead discovery methods for GPCR-based drug discovery. Creating leads from fragments is complicated, accurate, and dependable computational methods are employed to explore G protein-coupled receptor as a target via molecular dynamics simulations and the free energy perturbation approaches (MD/FEP). The overall knowledge of GPCR-mediated signaling can be expanded using such computational approaches.