Finding a better path to drug selectivity

Yuko Kawasaki, Ernesto Freire

Research output: Contribution to journalReview articlepeer-review

97 Scopus citations


Extremely high affinity and selectivity are two of the most sought-after properties of drug molecules. Selectivity has been difficult to achieve, especially for targets that belong to large families of structurally and functionally related proteins. There are essentially two ways by which selectivity can be improved during lead optimization: a chemical modification of the lead compound that improves the affinity towards the target to a higher extent than to off-target molecules; and a chemical modification that lowers the affinity of the lead compound towards off-target molecules. Maximal selectivity is achieved when both mechanisms can be combined synergistically. As we discuss here, analysis of several protease inhibitors that vary in a single functionality indicates that nonpolar functionalities preferentially follow the first mechanism, whereas polar functionalities follow the second, and that those features are imprinted in their thermodynamic signatures.

Original languageEnglish (US)
Pages (from-to)985-990
Number of pages6
JournalDrug Discovery Today
Issue number21-22
StatePublished - Nov 2011

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery


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