Molecular Properties and Structural Motifs Related to Pharmacological Promiscuity
Jens‐Uwe Peters · 2024
The chapter summarizes numerous studies linking molecular properties to pharmacological promiscuity, i.e., the unintended activity of compounds at non-therapeutic targets. In particular, the influence of basicity, ionization state, lipophilicity, and molecular weight is discussed. Emphasis is on basicity and ionization state, which are the main determinants of promiscuity in typical safety screens. In compounds with a basic center, some structural motifs lead to an increased propensity for promiscuity, whereas other motifs mitigate it. Basic compounds should be screened early in the drug discovery process against a small panel of predictive targets to prioritize leads for further optimization, identify promiscuity as a parameter for optimization, and avoid late attrition.