Next Article in Journal
Development and Optimization of a High Sensitivity LC-MS/MS Method for the Determination of Hesperidin and Naringenin in Rat Plasma: Pharmacokinetic Approach
Previous Article in Journal
Elaeagnus angustifolia Plant Extract Inhibits Epithelial-Mesenchymal Transition and Induces Apoptosis via HER2 Inactivation and JNK Pathway in HER2-Positive Breast Cancer Cells
Open AccessArticle

Coupling of HSP72 α-Helix Subdomains by the Unexpected Irreversible Targeting of Lysine-56 over Cysteine-17; Coevolution of Covalent Bonding

Molecular Bio-Computation & Drug Design Lab, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4000, South Africa
*
Author to whom correspondence should be addressed.
Molecules 2020, 25(18), 4239; https://doi.org/10.3390/molecules25184239
Received: 2 March 2020 / Revised: 2 April 2020 / Accepted: 6 April 2020 / Published: 16 September 2020
(This article belongs to the Section Computational and Theoretical Chemistry)
Covalent inhibition has recently gained a resurgence of interest in several drug discovery areas. The expansion of this approach is based on evidence elucidating the selectivity and potency of covalent inhibitors when bound to particular amino acids of a biological target. The unexpected covalent inhibition of heat shock protein 72 (HSP72) by covalently targeting Lys-56 instead of Cys-17 was an interesting observation. However, the structural basis and conformational changes associated with this preferential coupling to Lys-56 over Cys-17 remain unclear. To resolve this mystery, we employed structural and dynamic analyses to investigate the structural basis and conformational dynamics associated with the unexpected covalent inhibition. Our analyses reveal that the coupling of the irreversible inhibitor to Lys-56 is intrinsically less dynamic than Cys-17. Conformational dynamics analyses further reveal that the coupling of the inhibitor to Lys-56 induced a closed conformation of the nucleotide-binding subdomain (NBD) α-helices, in contrast, an open conformation was observed in the case of Cys-17. The closed conformation maintained the crucial salt-bridge between Glu-268 and Lys-56 residues, which strengthens the interaction affinity of the inhibitor nearly identical to adenosine triphosphate (ADP/Pi) bound to the HSP72-NBD. The outcome of this report provides a substantial shift in the conventional direction for the design of more potent covalent inhibitors. View Full-Text
Keywords: covalent MD simulation; HSP72; 8-N-benzyladenosine; coupling; principal component analysis covalent MD simulation; HSP72; 8-N-benzyladenosine; coupling; principal component analysis
Show Figures

Graphical abstract

MDPI and ACS Style

Aljoundi, A.; El Rashedy, A.; Appiah-Kubi, P.; Soliman, M.E.S. Coupling of HSP72 α-Helix Subdomains by the Unexpected Irreversible Targeting of Lysine-56 over Cysteine-17; Coevolution of Covalent Bonding. Molecules 2020, 25, 4239.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop