The Zn2 site of class B1 β-lactamase contains a conserved cysteine residue, Cys208 in NDM-1, required for Zn2+ binding. The disruption of Cys208 for Zn-coordination may effectively inhibit the hydrolysis activity of the enzyme against the β-lactam drugs. In principle, the development of covalent inhibitors targeting Cys208 could be a good approach; however, from my experience in submitting papers and proposals on this topic, it seems that this approach is generally NOT preferred and NOT welcome by most medicinal chemists. Any opinions or reasons for sharing?
Thank you.
I will speculate that the reason this approach is not favored is that your inhibitor would have to compete with the zinc ion for access to the Cys residue, and this might be difficult when zinc ion is not limiting in concentration. In contrast, you can gain a lot of affinity for the inhibitor by including a zinc-binding moiety.
Another issue that might concern people is obtaining the necessary selectivity for the Cys in NDM-1 over all the other Cys residues in the human body. This can be achieved one of two ways. (1) Start with an inhibitor with a high affinity for the target and that is already known to be highly selective, then add a weakly Cys-reactive electrophilic moiety (osimertinib is an example). (2) Create a mechanism-based inhibitor (also called a suicide substrate) that the enzyme activates to react with itself. This second approach won't work for NDM-1, however, because it is not active without the zinc ion, and with the zinc ion present the compound won't have access to the Cys residue.
I think zinc ion may actually be a limiting resource to bacteria under biologically relevant conditions, at least in some types of infections, so you may be able to make the first strategy work.
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