Analyzing Resistance to Design Selective Chemical Inhibitors for AAA Proteins.

ABSTRACT: Drug-like inhibitors are often designed by mimicking cofactor or substrate interactions with enzymes. However, as active sites are comprised of conserved residues, it is difficult to identify the critical interactions needed to design selective inhibitors. We are developing an approach, named RADD (resistance analysis during design), which involves engineering point mutations in the target to generate active alleles and testing compounds against them. Mutations that alter compound potency identify residues that make key interactions with the inhibitor and predict target-binding poses. Here, we apply this approach to analyze how diaminotriazole-based inhibitors bind spastin, a microtubule-severing AAA (ATPase associated with diverse cellular activities) protein. The distinct binding poses p

SUBMITTER: Pisa R 

PROVIDER: S-EPMC6754270 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature