Sphingosine kinase 1 (SK1) allosteric inhibitors that target the dimerization site |
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| Institution: | 1. Department of Computational Science and Engineering, Bogazici University, 34342 Bebek, Istanbul, Turkey;2. Department of Chemical Engineering, Bogazici University, 34342 Bebek, Istanbul, Turkey;1. Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine;2. Department of Technology of Biologically Active Substances, Pharmacy and Biotechnology, Lviv Polytechnic National University, Bandery 12, Lviv 79013, Ukraine;3. Department of Organic Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, Poznan 60-780, Poland;1. Environmental Carcinogenesis & Proteomics Laboratory, Food, Drug & Chemical Toxicology Group, VishvigyanBhawan 31, Mahatma Gandhi Marg, Lucknow, 226001, Uttar Pradesh, India;2. Department of Bioengineering, Faculty of Engineering, Integral University, Lucknow, 226026, Uttar Pradesh, India;3. From the Department of Biology, Osaka Dental University, Hirakata 573-1121,;4. the Department of Virus Research, Institute for Frontier Life and Medical Sciences (InFRONT),;12. Mammalian Regulatory Network, Graduate School of Biostudies, Kyoto University, Kyoto 606-8507,;5. the Graduate School of Frontier Biosciences, Osaka University, Suita 565-0871, and;6. the Advanced ICT Research Institute Kobe, National Institute of Information and Communications Technology, Kobe 651-2492, Japan |
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| Abstract: | The sphingosine kinase 1 (SK1)/sphingosine-1-phosphate (S1P) signaling pathway is a crucial target for numerous human diseases from cancer to cardiovascular diseases. However, available SK1 inhibitors that target the active site suffer from poor potency, selectivity and pharmacokinetic properties. The selectivity issue of the kinases, which share a highly-conserved ATP-pocket, can be overcome by targeting the less-conserved allosteric sites. SK1 is known to function minimally as a dimer; however, the crystal structure of the SK1 dimer has not been determined. In this study, a template-based algorithm implemented in PRISM was used to predict the SK1 dimer structure and then the possible allosteric sites at the dimer interface were determined via SiteMap. These sites were used in a virtual screening campaign that includes an integrated workflow of structure-based pharmacophore modeling, virtual screening, molecular docking, re-screening of common scaffolds to propose a series of compounds with different scaffolds as potential allosteric SK1 inhibitors. Finally, the stability of the SK1-ligand complexes was analyzed by molecular dynamics simulations. As a final outcome, ligand 7 having a 4,9-dihydro-1H-purine scaffold and ligand 12 having a 2,3,4,9-tetrahydro-1H-β-carboline scaffold were found to be potential selective inhibitors for SK1. |
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| Keywords: | sphingosine kinase 1 allosteric inhibitor docking virtual screening pharmacophore modeling molecular dynamics |
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