Aryl Thiophenyl-Sulfonamides as potential therapeutics for multiple sclerosis: PAMPA-based pharmacokinetic predictions and multiligand screening against S1PR3

Multiple sclerosis (MS) is a chronic and progressive neurological disease with significant global economic impact, with annual costs per patient ranging from US$16.614 to US$72.744. This scenario has driven the search for new therapeutic agents to enhance efficacy and reduce treatment-associated expenses. This study evaluated the activity of a series of Thiophenyl-Sulfonamide derivatives (TSD1–8) against MS by targeting the Sphingosine 1-phosphate receptor 3 (S1PR3) using a multiligand virtual screening approach. Computational predictions of cell permeability and metabolic stability parameters related to blood-brain barrier (BBB) penetration were conducted using machine learning-based online tools. Additionally, pharmacodynamic simulations involving molecular docking and molecular dynamics were employed to analyze interactions between TSD derivatives and the S1PR3 receptor. Pharmacokinetic analysis suggested that the TSD8 derivative presents Madin-Darby Canine Kidney (MDCK) cell permeability values around 10⁻⁵ cm/s, indicating favorable BBB penetration. However, CYP450-mediated N -dealkylation may reduce metabolic stability and oral bioavailability. Docking results revealed that TSD8 binds to the S1PR3 active site mainly via hydrophobic interactions with key residues such as Tyr92, Phe119, and Trp256. These interactions remained stable over 200 ns of molecular dynamics simulations. Altogether, the in silico findings suggest that TSD8 may act as a functional antagonist of S1PR3, showing potential as a promising candidate for MS treatment.