Finding a better path to drug selectivity

Yuko Kawasaki, Ernesto I Freire

Research output: Contribution to journalArticle

Abstract

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
Volume16
Issue number21-22
DOIs
StatePublished - Nov 2011

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Pharmaceutical Preparations
Protease Inhibitors
Thermodynamics
Lead
Proteins

ASJC Scopus subject areas

  • Drug Discovery
  • Pharmacology

Cite this

Finding a better path to drug selectivity. / Kawasaki, Yuko; Freire, Ernesto I.

In: Drug Discovery Today, Vol. 16, No. 21-22, 11.2011, p. 985-990.

Research output: Contribution to journalArticle

Kawasaki, Yuko ; Freire, Ernesto I. / Finding a better path to drug selectivity. In: Drug Discovery Today. 2011 ; Vol. 16, No. 21-22. pp. 985-990.
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