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Evaluating hydrophobic galactonoamidines as transition state analogs for enzymatic β-galactoside hydrolysis |
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| Institution: | 1. State Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation Center of Chemistry for Life Sciences, Department of Biochemistry, Nanjing University, Nanjing 210093, PR China;2. Center for Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai 200444, PR China;1. Institute of Chemical Biology, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.;2. Membrane Biophysics Platform, Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.;3. Division of Molecular Biology, Imperial College London, South Kensington Campus, London SW7 2AZ, U.K.;1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia;2. Biological Faculty, Lomonosov Moscow State University, Moscow 119992, Russia;3. Toxicology and Pharmacology, University of Leuven, Leuven 3000, Belgium;4. National Research University Higher School of Economics, Moscow, 101000, Russia |
| Abstract: | A spectroscopic examination of six galactonoamidines with inhibition constants and efficacy in the low nanomolar concentration range (Ki = 6–11 nM, IC50 = 12–36 nM) suggested only two of them as putative transition state analogs for the hydrolysis of β-galactosides by β-galactosidase (A. oryzae). A rationale for the experimental results was elaborated using docking and molecular dynamics studies. An analysis of the combined observations reveals several common factors of the compounds suggested as transition state analogs (TSAs): the putative TSAs have a similar orientation in the active site; show conserved positioning of the glycon; display a large number of H-bond interactions toward the catalytically active amino acid residues via their glycon; and exhibit hydrophobic interactions at the outer rim of the active site with small changes of the position and orientation of their respective aglycons. |
| Keywords: | Inhibitor Transition state analogs Galactonoamidines Molecular dynamics Hydrophobic loops |
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