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A systematic methodology for large scale compound screening: A case study on the discovery of novel S1PL inhibitors.
J Mol Graph Model. 2016 Jan; 63:110-24.JM

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Deniz U
Chemical Engineering Department, Bogazici University, Bebek 34342, Istanbul, Turkey.
Ozkirimli E
Chemical Engineering Department, Bogazici University, Bebek 34342, Istanbul, Turkey.
Ulgen KO
Chemical Engineering Department, Bogazici University, Bebek 34342, Istanbul, Turkey. Electronic address: ulgenk@boun.edu.tr.

MeSH

Aldehyde-LyasesAmino Acid MotifsBinding SitesCatalytic DomainCytochrome P-450 Enzyme SystemERG1 Potassium ChannelEnzyme InhibitorsEther-A-Go-Go Potassium ChannelsHigh-Throughput Screening AssaysHumansKineticsLigandsLysophospholipidsMolecular Docking SimulationMolecular Dynamics SimulationMolecular Sequence DataProtein BindingProtein Structure, SecondarySmall Molecule LibrariesSphingosineStatic ElectricityStructure-Activity RelationshipThermodynamicsUser-Computer Interface

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26724452

Citation

Deniz, Utku, et al. "A Systematic Methodology for Large Scale Compound Screening: a Case Study On the Discovery of Novel S1PL Inhibitors." Journal of Molecular Graphics & Modelling, vol. 63, 2016, pp. 110-24.
Deniz U, Ozkirimli E, Ulgen KO. A systematic methodology for large scale compound screening: A case study on the discovery of novel S1PL inhibitors. J Mol Graph Model. 2016;63:110-24.
Deniz, U., Ozkirimli, E., & Ulgen, K. O. (2016). A systematic methodology for large scale compound screening: A case study on the discovery of novel S1PL inhibitors. Journal of Molecular Graphics & Modelling, 63, 110-24. https://doi.org/10.1016/j.jmgm.2015.11.004
Deniz U, Ozkirimli E, Ulgen KO. A Systematic Methodology for Large Scale Compound Screening: a Case Study On the Discovery of Novel S1PL Inhibitors. J Mol Graph Model. 2016;63:110-24. PubMed PMID: 26724452.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A systematic methodology for large scale compound screening: A case study on the discovery of novel S1PL inhibitors. AU - Deniz,Utku, AU - Ozkirimli,Elif, AU - Ulgen,Kutlu O, Y1 - 2015/11/12/ PY - 2015/08/05/received PY - 2015/10/07/revised PY - 2015/11/06/accepted PY - 2016/1/3/entrez PY - 2016/1/3/pubmed PY - 2016/10/12/medline KW - Efficiency indices (BEI & LLE) KW - Multiple sclerosis (MS) disease KW - Sphingosine 1-phosphate lyase (S1PL) KW - Substructure search KW - Virtual screening SP - 110 EP - 24 JF - Journal of molecular graphics & modelling JO - J Mol Graph Model VL - 63 N2 - 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. SN - 1873-4243 UR - https://www.unboundmedicine.com/medline/citation/26724452/A_systematic_methodology_for_large_scale_compound_screening:_A_case_study_on_the_discovery_of_novel_S1PL_inhibitors_ DB - PRIME DP - Unbound Medicine ER -