Journal of Computer-Aided Molecular Design

, Volume 33, Issue 9, pp 799–815 | Cite as

Discovery of a nanomolar inhibitor of the human glyoxalase-I enzyme using structure-based poly-pharmacophore modelling and molecular docking

  • Nizar A. Al-Shar’iEmail author
  • Qosay A. Al-Balas
  • Rand A. Al-Waqfi
  • Mohammad A. Hassan
  • Amer E. Alkhalifa
  • Nehad M. Ayoub


The glyoxalase-I (GLO-I) enzyme, which is the initial enzyme of the glyoxalase system that is responsible for the detoxification of cytotoxic α-ketoaldehydes, such as methylglyoxal, has been approved as a valid target in cancer therapy. Overexpression of GLO-I has been observed in several types of carcinomas, including breast, colorectal, prostate, and bladder cancer. In this work we aimed to identify potential GLO-I inhibitors via employing different structure-based drug design techniques including structure-based poly-pharmacophore modelling, virtual screening, and molecular docking. Poly-pharmacophore modelling was applied in this study in order to thoroughly explore the binding site of the target enzyme, thereby, revealing hits that could bind in a nonconventional way which can pave the way for designing more potent and selective ligands with novel chemotypes. The modelling phase has resulted in the selection of 31 compounds that were biologically evaluated against human GLO-I enzyme. Among the tested set, seven compounds showed excellent inhibitory activities with IC50 values ranging from 0.34 to 30.57 μM. The most active compound (ST018515) showed an IC50 of 0.34 ± 0.03 μM, which, compared to reported GLO-I inhibitors, can be considered a potent inhibitor, making it a good candidate for further optimization towards designing more potent GLO-I inhibitors.


Glyoxalase-I Zinc binding Anticancer Poly-pharmacophore modelling Molecular docking 



This work was funded by the Deanship of Scientific Research at Jordan University of Science and Technology, Grant Number (20170288).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10822_2019_226_MOESM1_ESM.docx (46 kb)
Supplementary file1 (DOCX 46 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Medicinal Chemistry and Pharmacognosy, Faculty of PharmacyJordan University of Science and TechnologyIrbidJordan
  2. 2.Department of Clinical Pharmacy, Faculty of PharmacyJordan University of Science and TechnologyIrbidJordan

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