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Appropriate tuning of binding selectivity is a primary objective in the discovery and optimization of a compound on the path toward developing a drug. The environment in which drugs act is complex, with many potential interaction partners. Proteins, DNA, RNA, lipids, sugars, metabolites, and other small molecules all have the potential to interact with a drug, and in many cases these unexpected interactions lead to undesired and often severe side effects. Conversely, the ability to interact with multiple targets or drug resistance mutants can be advantageous in certain contexts. Designing a drug with the appropriate balance of avoidance of undesirable targets (narrow selectivity) and coverage of one or more targets of interest (broad selectivity, also referred to as promiscuity) is a continual drug development challenge. In many cases this objective is attained through trial and error, but there are rational approaches that …