Winning the arms race by improving drug discovery against mutating targets

Enzymes are often excellent drug targets. Yet drug pressure on an enzyme target often fosters the rise of cells with resistance-conferring mutations, some of which may compromise fitness and others that compensate to restore fitness. This review presents, first, a structural analysis of a diverse group of wild-type and mutant enzyme targets and, second, an in-depth analysis of five diverse targets to elucidate a broader perspective of the effects of resistance-conferring mutations on protein or organismal fitness. The structural analysis reveals that resistance-conferring mutations may introduce steric hindrance or eliminate critical interactions, as expected, but that they may also have indirect effects such as altering protein dynamics and enzyme kinetics. The structure-based development of the latest generation of inhibitors targeting HIV reverse transcriptase, P. falciparum and S. aureus dihydrofolate reductase, neuraminidase, and epithelial growth factor receptor (EGFR) tyrosine kinase, is highlighted to emphasize lessons that may be applied to future drug discovery to overcome mutation-induced resistance. Successful next-generation drugs tend to be more flexible and exploit a greater number of interactions mimicking those of the substrate with conserved residues.