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Updated: Dec 26, 2025

Quadruple-Checkerboard: A Modification of the Three-Dimensional Checkerboard for Studying Drug Combinations
Published on: July 24, 2021
Combining Allosteric and Orthosteric Drugs to Overcome Drug Resistance
1State Key Laboratory of Oncogenes and Related Genes, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; The Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia.
Abstract:
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.
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