Winning the Arms Race by Improving Drug Discovery against Mutating Targets

This review looks at structural analysis of enzyme targets that have mutations which confer resistance to a small molecule drug. By comparing wild-type and resistant mutant enzymes they can observe how drug resistance commonly develops, which can be valuable for designing second generation drugs that are less prone to create a rise in resistance. A broad range of enzymes are included in their initial studies, and several biologically relevant targets are examined in greater detail. Overall, the take home message is that drug-resistance mutations often change the steric hindrance or binding site of the small molecule drug targets, and can have an effect on enzyme activity. Small molecules that are designed to mimic the natural substrate interactions or alter enzyme kinetics are more likely to be effective against resistance-developing mutants. They propose that small molecule flexibility and structural freedom can also aid in overcoming resistance.