COMPUTATIONAL SCREENING AND BINDING ANALYSIS OF NOVEL EMERGING SMALL-MOLECULE S1PR1 MODULATORS FOR MULTIPLE SCLEROSIS

Abstract

Aim: Multiple sclerosis (MS) is a chronic neurological disorder that develops when the body's immune system mistakenly attacks the central nervous system. As a result, the myelin coating that envelops nerve fibers is damaged, which eventually impairs brain-to-body communication. This eventually results in increasing neurological issues like cognitive decline, coordination issues, and muscular weakening. Inflammation, demyelination, and axonal degeneration are the disease's hallmarks, which make it complicated and difficult to treat. Instead of offering a full recovery, current treatment approaches mostly focus on treatments which will modify the disease, which try to slow the course of the illness and regulate immune system activity. Treatments that target sphingosine-1-phosphate receptors (S1PRs), particularly S1PR1, have demonstrated significant potential. These receptors are crucial for controlling lymphocyte migration. In order to lessen inflammatory damage, autoreactive immune cells can be stopped from leaving lymph nodes and entering the CNS by adjusting S1PR1 activity. The first oral medication authorized for the treatment of multiple sclerosis was fingolimod (FTY720), which marked a significant departure from injectable treatments. It has been shown to be successful in lowering relapse rates and functions as a functional modulator of S1PR1. Furthermore, the medication has to be phosphorylated by the body in order to become active, which might have an impact on its overall effectiveness and response consistency among various people. Given these constraints, it is imperative to investigate alternative S1PR1 small-molecule modulators that have better pharmacological and safety characteristics. A computational method was employed in this investigation to find possible compounds that could function as efficient S1PR1 modulators. Molecular docking methods were used to investigate compounds that were selected based on their structural similarity to fingolimod in order to assess their binding interactions with the target protein. Promising possibilities were identified by closely examining the stability and intensity of these interactions. Additionally, significant drug-like characteristics such absorption, distribution, metabolism, and excretion were evaluated by ADME study. These substances might be promising avenues for the creation of safer and more efficient multiple sclerosis medicines. Keywords— Multiple Sclerosis; S1PR1; FTY720; conformation-Based therapeutic Design; Molecular Docking; Auto Dock Vina; Small-Molecule Modulators

RESULTS - The molecular docking study revealed that all selected compounds showed favourable binding with the S1PR1 receptor, confirming the suitability of the designed scaffold for Multiple Sclerosis drug targeting. Among them, ligand 6 demonstrated the strongest and most stable interaction, making it a promising lead candidate for further experimental validation.

CONCLUSION : With the greatest binding affinity and BBB permeability, ligand 6 is the most effective of the six discovered ligands. We advise using in vivo investigations to confirm these results.