Journal of Computer-Aided Molecular Design

, Volume 33, Issue 4, pp 405–417 | Cite as

Discovery of novel inhibitors of human galactokinase by virtual screening

  • Xin Hu
  • Ya-Qin Zhang
  • Olivia W. Lee
  • Li Liu
  • Manshu Tang
  • Kent Lai
  • Matthew B. Boxer
  • Matthew D. Hall
  • Min ShenEmail author


Classic Galactosemia is a potentially lethal autosomal recessive metabolic disorder caused by deficient galactose-1-phosphate uridyltransferase (GALT) that results in the buildup of galactose-1-phosphate (gal-1-p) in cells. Galactokinase (GALK1) is the enzyme responsible for converting galactose into gal-1-p. A pharmacological inhibitor of GALK1 is hypothesized to be therapeutic strategy for treating galactosemia by reducing production of gal-1-p. In this study, we report the discovery of novel series of GALK1 inhibitors by structure-based virtual screening (VS). Followed by an extensive structural modeling and binding mode analysis of the active compounds identified from quantitative high-throughput screen (qHTS), we developed an efficient pharmacophore-based VS approach and applied for a large-scale in silico database screening. Out of 230,000 compounds virtually screened, 350 compounds were cherry-picked based on multi-factor prioritization procedure, and 75 representing a diversity of chemotypes exhibited inhibitory activity in GALK1 biochemical assay. Furthermore, a phenylsulfonamide series with excellent in vitro ADME properties was selected for downstream characterization and demonstrated its ability to lower gal-1-p in primary patient fibroblasts. The compounds described herein should provide a starting point for further development of drug candidates for the GALK1 modulation in the Classic Galactosemia.


Galactosemia GALK1 Quantitative high-throughput screening Virtual screening Pharmacophore 



We thank Danielle van Leer, Misha Itkin, Crystal McKnight, Christopher LeClair and Paul Shinn for assistance with compound management. We also thank Pranav Shah and Amy Wang for assistance in vitro ADME assays. This research was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research Grant U54MH084681 and the Intramural Research Program of the National Center for Advancing Translational Sciences at the National Institutes of Health. Research Grant support to K.L. include R03MH085689 and R01HD074844-2.

Supplementary material

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Copyright information

© This is a U.S. government work and its text is not subject to copyright protection in the United States; however, its text may be subject to foreign copyright protection 2019

Authors and Affiliations

  • Xin Hu
    • 1
  • Ya-Qin Zhang
    • 1
  • Olivia W. Lee
    • 1
  • Li Liu
    • 1
  • Manshu Tang
    • 2
  • Kent Lai
    • 2
  • Matthew B. Boxer
    • 1
    • 3
  • Matthew D. Hall
    • 1
  • Min Shen
    • 1
    Email author
  1. 1.NIH Chemical Genomics Center, National Center for Advancing Translational SciencesNational Institutes of HealthRockvilleUSA
  2. 2.Division of Medical Genetics, Department of PediatricsUniversity of Utah School of MedicineSalt Lake CityUSA
  3. 3.Nexus Discovery AdvisorsFrederickUSA

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