Combining Allosteric and Orthosteric Drugs to Overcome Drug Resistance

Traditional drugs target protein orthosteric sites; drug resistance inevitably develops due to Darwinian selection pressure posed by the therapeutics. Drug resistance triggers disease relapse and causes great losses to the drug discovery processes. It also constitutes a key threat to global health and a major challenge to modern medicine. Allosteric drugs target sites distinct from those of orthosteric drugs. They modulate the functions of orthosteric drugs and can resensitize resistant targets. Double targeting at allosteric and orthosteric sites can overcome resistance and improve pharmacological effectiveness. Combinatorial treatments with allosteric and orthosteric drugs provide a novel strategy against 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. 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. a pocket spatially and topologically distinct from orthosteric sites. Perturbations at allosteric sites caused by factors such as mutations or binding by ligands known as allosteric modulators can modulate the activity of orthosteric sites. a compound that binds to allosteric sites and modulates the activity of orthosteric sites. a pocket where endogenous ligands and substrates bind. a compound that binds to orthosteric sites and modulates the activity of target proteins through direct competition with endogenous ligands or substrate molecules. drug resistance resulting from the abnormal activation or rewiring of the compensatory pathways, which can bypass the requirements for the original drug targets, enable pathogenic signal transduction, and reduce therapeutic agent efficacy. drug resistance triggered by changes in the original protein targets, such as mutations or other lesions that modify their biological and medicinal properties by either inducing direct steric clash or altering the structural ensemble. These changes hinder the binding or the functions of drug molecules, making them ineffective.