Computational Approaches in Evaluating the 5-HT Subtype Receptor Mechanism of Action for Developing Novel Chemical Entities
Authors: Chauhan Arushi , Avti Pramod K . 
Published: November 2024

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.