Evaluating hydrophobic galactonoamidines as transition state analogs for enzymatic β-galactoside hydrolysis
Document Type
Article - Abstract Only
Publication Date
2018
Keywords
Inhibitor, Transition state analogs, Galactonoamidines, β-Galactosidase, Molecular dynamics, Hydrophobic loops
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.
Citation
Pickens, J., Mills, L., Wang, F., & Striegler, S. (2018). Evaluating hydrophobic galactonoamidines as transition state analogs for enzymatic β-galactoside hydrolysis. Bioorganic Chemistry, 77, 144-151. https://doi.org/10.1016/j.bioorg.2018.01.012
Comments
Support of this research to F. W. by the National Institutes of Health(1R01GM120578), to S.S. from the National Science Foundation (CHE-1305543) and the Arkansas Biosciences Institute, and to L.G.M by a Statewide Undergraduate Research Fellowship from the Arkansas Department of Higher Education and an Undergraduate Research Fellowship from the University of Arkansas Honors College are gratefully acknowledged. The facilities used in this study were supported by Grant Number P30 GM103450 from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health (NIH). The molecular dynamic simulations were performed in the Arkansas High-Performance Computing Center, which is supported by the National Science Foundation (ACI0722625, ACI0959124, ACI0963249, and ACI0918970) and the Division of Science and Technology at the Arkansas Economic Development Commission.