Targeting post-translationally modified cysteine by covalent inhibitors at diverse redox conditions using computational approaches

Abstract

Cysteine is a unique amino acid which can be subject to diverse redox chemistry, undergoing post-translational modifications (PTMs). Some functionally-relevant examples include cysteine S-sulfenylation and S-nitrosylation. These modifications play a crucial role in redox signalling, they can modulate the structure and dynamics of proteins, and they can be targets for molecular probes or drug-like molecules. This thesis focuses on determining the effects of functionally important cysteine modifications on the structure, dynamics and energetics of several important cancer drug targets and using structure-based approaches to design small molecular probes which can capture sulfenic acid cysteine. Specifically, this work proposes novel covalent inhibitors which capture S-sulfenylated cysteine C797 in the epidermal growth factor receptor (EGFR) oncogenic mutant L858R/T790M, and oncogenic driver mutation G12C of K-Ras GTPase. Furthermore, it offers the mechanistic insight into unfolding and aggregation of tumour suppressor p16, which is promoted by the oxidation of cysteine C72. Collectively, the results presented in this work provide mechanistic insights into roles exerted by reactive cysteine thiols at atomistic level of detail, and the foundations for development of potential anticancer therapeutics and a novel way to target oxidation-prone cysteine residues in cancer related proteins.