Designed dualsteric modulators: A novel route for drug discovery

• Published in: Drug discovery today 2024-10, Vol.29 (10), p.104141, Article 104141
• Main Authors: Li, Nuan, Zheng, Guodong, Fu, Lili, Liu, Ning, Chen, Ting, Lu, Shaoyong
• Format: Article
• Language: English
• Subjects: allosteric modulators; Allosteric Regulation - drug effects; Allosteric Site; Animals; Drug Design; Drug Discovery - methods; G protein-coupled receptors; Humans; kinase inhibitors; orthosteric site; Structure-Activity Relationship
• ISSN: 1359-6446; 1878-5832; 1878-5832
• DOI: 10.1016/j.drudis.2024.104141

•Dualsteric modulators represent a rising technology in the field of drug design.•The binding modes of dualsteric modulators with their targets are highlighted.•Clinical application of dualsteric modulators requires more optimization. Orthosteric and allosteric modulators, which constitute the majority of current drugs, bind to the orthosteric and allosteric sites of target proteins, respectively. However, the clinical efficacy of these agents is frequently compromised by poor selectivity or reduced potency. Dualsteric modulators feature two linked pharmacophores that bind to orthosteric and allosteric sites of the target proteins simultaneously, thereby offering a promising avenue to achieve both potency and specificity. In this review, we summarize recent structures available for dualsteric modulators in complex with their target proteins, elucidating detailed drug–target interactions and dualsteric action patterns. Moreover, we provide a design and optimization strategy for dualsteric modulators based on structure-based drug design approaches.