title: Evaluation and Optimization ofin silicodesigned Sphingosine-1-Phosphate (S1P) Receptor Subtype 1 Modulators for the Management of Multiple Sclerosis.
abstract: Multiple Sclerosis (MS) is a chronic autoimmune disorder affecting the Central Nervous System (CNS) through inflammation, demyelination and neurodegeneration. Sphingosine-1-phosphate receptor (S1PR1) modulators have been approved for the management of MS. Phosphorylated fingolimod mimics endogenous sphingosine-1-phosphate (S1P), a bioactive lipid that regulates remyelination and cell injury. Amiselimod was developed as a successor of fingolimod, with more specificity for S1PR1, and showed promising results until phase 2 clinical trials. This study utilized the fingolimod and amiselimod scaffolds, together with their critical binding interactions for the S1PR1 Ligand Binding Pocket, as templates for thein silico de novodesign of high efficiency binding Lipinski rule-compliant molecules. A rigorous selection process identified two molecules, Molecules 003 and 019, deriving from fingolimod and amiselimod, respectively, which were deemed most suitable for further optimization.
authors.affiliation: University of Malta, Department of Pharmacy, Malta.
authors.forename: Daphne H
authors.initials: DH
authors.lastname: Gusman
authors.affiliation: University of Malta, Department of Pharmacy, Malta.
authors.forename: Claire
authors.initials: C
authors.lastname: Shoemake
mesh_terms: D000465:Algorithms; D000818:Animals; D018360:Crystallography, X-Ray; D015195:Drug Design; D000068876:Fingolimod Hydrochloride / Q000737:chemistry; D006801:Humans; D007155:Immunologic Factors / Q000737:chemistry / Q000627:therapeutic use*; D008246:Lysophospholipids / Q000378:metabolism*; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000378:metabolism*; D017433:Protein Structure, Secondary; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D007155:Immunologic Factors; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
keywords: Amiselimod; Drug Design; Fingolimod; Multiple Sclerosis; Protomol Generation; Sphingosine-1-phosphate Receptor 1