Cell Biochemistry and Biophysics

, Volume 77, Issue 3, pp 203–211 | Cite as

Selective Covalent Inhibition of “Allosteric Cys121” Distort the Binding of PTP1B Enzyme: A Novel Therapeutic Approach for Cancer Treatment

  • Shama Khan
  • Imane Bjij
  • Mahmoud E. S. SolimanEmail author
Original Paper


Covalent inhibition targeting noncatalytic residues is rapidly gaining attention in drug discovery. Protein tyrosine phosphatases 1B (PTP1B) is an attractive target for therapeutic interventions in cancer and other diseases. Two binding sites of PTP1B enzyme were identified, catalytic and allosteric. The catalytic site is deep and narrow which protects the active site amino acid residue Cys215 from covalent inhibition, whereas the allosteric site is more hydrophobic and less conserved with Cys121 residue, to which covalent inhibitors can bind. A recent experimental report highlighted that a highly selective inhibitor, 73U, was found to bind covalently in the allosteric region of PTP1B enzyme. Using a robust covalent simulations protocol which was developed in-house, we explore the origin and impact of covalent inhibition upon inhibitor binding to allosteric site. For this, covalently bound and apo enzymes were investigated. Results revealed that allosteric covalent inhibition has ensued in a significant disturbance in the overall network of interaction between Cys121 and other nearby residues, more specifically Tyr124 and His214. The covalent inhibition also exhibited better protein stability as evident from positive correlation between residues in the allosteric site and multiple van der Waal, hydrogen bond and ionic interactions. Surface analysis revealed an increase in the accessible surface area in order to facilitate for the covalent inhibitor to sink in. These findings indicate that exploring allosteric covalent mechanism of PTP1B enzyme offers an opportunity to develop novel PTP1B covalent inhibitors with high potency and selectivity for cancer and other diseases.


Allosteric covalent inhibition PTP1B enzyme Covalent molecular dynamic simulations Protein kinases 



I would like to acknowledge the Center for High Computing Performance (CHPC), Cape Town, for resources and technical support as well as the College of Health Sciences for their financial support.

Compliance With Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12013_2019_882_MOESM1_ESM.docx (4.2 mb)
Supplementary Information


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Shama Khan
    • 1
  • Imane Bjij
    • 1
    • 2
  • Mahmoud E. S. Soliman
    • 1
    Email author
  1. 1.Molecular Bio-Computation & Drug Design Lab, School of Health SciencesUniversity of KwaZulu-NatalDurbanSouth Africa
  2. 2.Département de Chimie, Faculté des Sciences SemlaliaUniversité Cadi AyyadMarrakechMorocco

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