Combining Allosteric and Orthosteric Drugs to Overcome Drug Resistance

Historically, most drugs target protein orthosteric sites. The gradual emergence of resistance hampers their therapeutic effectiveness, posing a challenge to drug development. Coadministration of allosteric and orthosteric drugs provides a revolutionary strategy to circumvent drug resistance, as drugs targeting the topologically distinct allosteric sites can restore or even enhance the efficacy of orthosteric drugs. Here, we comprehensively review the latest successful examples of such combination treatments against drug resistance, with a focus on their modes of action and the underlying structural mechanisms. Our work supplies an innovative insight into such promising methodology against the recalcitrant drug resistance conundrum and will be instructive for future clinical therapeutics.