2 research outputs found
Rebuttal to Correspondence on “Endocytosis-Mediated Transport of Pb in Rat Blood Cells”
Rebuttal to Correspondence
on “Endocytosis-Mediated
Transport of Pb in Rat Blood Cells
Identification of Covalent Binding Sites Targeting Cysteines Based on Computational Approaches
Covalent
drugs have attracted increasing attention in recent years
due to good inhibitory activity and selectivity. Targeting noncatalytic
cysteines with irreversible inhibitors is a powerful approach for
enhancing pharmacological potency and selectivity because cysteines
can form covalent bonds with inhibitors through their nucleophilic
thiol groups. However, most human kinases have multiple noncatalytic
cysteines within the active site; to accurately predict which cysteine
is most likely to form covalent bonds is of great importance but remains
a challenge when designing irreversible inhibitors. In this work,
FTMap was first applied to check its ability in predicting covalent
binding site defined as the region where covalent bonds are formed
between cysteines and irreversible inhibitors. Results show that it
has excellent performance in detecting the hot spots within the binding
pocket, and its hydrogen bond interaction frequency analysis could
give us some interesting instructions for identification of covalent
binding cysteines. Furthermore, we proposed a simple but useful covalent
fragment probing approach and showed that it successfully predicted
the covalent binding site of seven targets. By adopting a distance-based
method, we observed that the closer the nucleophiles of covalent warheads
are to the thiol group of a cysteine, the higher the possibility that
a cysteine is prone to form a covalent bond. We believe that the combination
of FTMap and our distance-based covalent fragment probing method can
become a useful tool in detecting the covalent binding site of these
targets