Exploring Extended Warheads toward Developing Cysteine-Targeted Covalent Kinase Inhibitors.

In designing covalent kinase inhibitors (CKIs), the inclusion of electrophiles as attacking warheads demands careful choreography, ensuring not only their presence on the scaffold moiety but also their precise interaction with nucleophiles in the binding sites. Given the limited number of known electrophiles, exploring adjacent chemical space to broaden the palette of available electrophiles capable of covalent inhibition is desirable. Here, we systematically analyze the characteristics of warheads and the corresponding adjacent fragments for use in CKI design.

Deep generative models of protein structure uncover distant relationships across a continuous fold space.

Our views of fold space implicitly rest upon many assumptions that impact how we analyze, interpret and understand protein structure, function and evolution. For instance, is there an optimal granularity in viewing protein structural similarities (e.g.

Advances in reversible covalent kinase inhibitors.

Reversible covalent kinase inhibitors (RCKIs) are a class of novel kinase inhibitors attracting increasing attention because they simultaneously show the selectivity of covalent kinase inhibitors yet avoid permanent protein-modification-induced adverse effects. Over the last decade, RCKIs have been reported to target different kinases, including Atypical group of kinases. Currently, three RCKIs are undergoing clinical trials.