title: A systematic methodology for large scale compound screening: A case study on the discovery of novel S1PL inhibitors.
abstract: Decrease in sphingosine 1-phosphate (S1P) concentration induces migration of pathogenic T cells to the blood stream, disrupts the CNS and it is implicated in multiple sclerosis (MS), a progressive inflammatory disorder of the central nervous system (CNS), and Alzheimer's disease (AD). A promising treatment alternative for MS and AD is inhibition of the activity of the microsomal enzyme sphingosine 1-phosphate lyase (S1PL), which degrades intracellular S1P. This report describes an integrated systematic approach comprising virtual screening, molecular docking, substructure search and molecular dynamics simulation to discover novel S1PL inhibitors. Virtual screening of the ZINC database via ligand-based and structure-based pharmacophore models yielded 10000 hits. After molecular docking, common substructures of the top ranking hits were identified. The ligand binding poses were optimized by induced fit docking. MD simulations were performed on the complex structures to determine the stability of the S1PL-ligand complex and to calculate the binding free energy. Selectivity of the selected molecules was examined by docking them to hERG and cytochrome P450 receptors. As a final outcome, 15 compounds from different chemotypes were proposed as potential S1PL inhibitors. These molecules may guide future medicinal chemistry efforts in the discovery of new compounds against the destructive action of pathogenic T cells.
authors.affiliation: Chemical Engineering Department, Bogazici University, Bebek 34342, Istanbul, Turkey.
authors.forename: Utku
authors.initials: U
authors.lastname: Deniz
authors.affiliation: Chemical Engineering Department, Bogazici University, Bebek 34342, Istanbul, Turkey.
authors.forename: Elif
authors.initials: E
authors.lastname: Ozkirimli
authors.affiliation: Chemical Engineering Department, Bogazici University, Bebek 34342, Istanbul, Turkey. Electronic address: ulgenk@boun.edu.tr.
authors.forename: Kutlu O
authors.initials: KO
authors.lastname: Ulgen
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020816:Amino Acid Motifs; D001665:Binding Sites; D020134:Catalytic Domain; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors / Q000737:chemistry*; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008246:Lysophospholipids / Q000737:chemistry*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D054852:Small Molecule Libraries / Q000737:chemistry*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000737:chemistry; D055672:Static Electricity; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D008024:Ligands; D008246:Lysophospholipids; D054852:Small Molecule Libraries; C060506:sphingosine 1-phosphate; D003577:Cytochrome P-450 Enzyme System; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine
keywords: Efficiency indices (BEI & LLE); Multiple sclerosis (MS) disease; Sphingosine 1-phosphate lyase (S1PL); Substructure search; Virtual screening