Quarterly Reviews of Biophysics



Essay

Designing ligands to bind proteins


George M. Whitesides a1c1 and Vijay M. Krishnamurthy a1
a1 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

Article author query
whitesides gm   [PubMed][Google Scholar] 
krishnamurthy vm   [PubMed][Google Scholar] 

Abstract

The ability to design drugs (so-called ‘rational drug design’) has been one of the long-term objectives of chemistry for 50 years. It is an exceptionally difficult problem, and many of its parts lie outside the expertise of chemistry. The much more limited problem – how to design tight-binding ligands (rational ligand design) – would seem to be one that chemistry could solve, but has also proved remarkably recalcitrant. The question is ‘Why is it so difficult?’ and the answer is ‘We still don't entirely know’. This perspective discusses some of the technical issues – potential functions, protein plasticity, enthalpy/entropy compensation, and others – that contribute, and suggests areas where fundamental understanding of protein–ligand interactions falls short of what is needed. It surveys recent technological developments (in particular, isothermal titration calorimetry) that will, hopefully, make now the time for serious progress in this area. It concludes with the calorimetric examination of the association of a series of systematically varied ligands with a model protein. The counterintuitive thermodynamic results observed serve to illustrate that, even in relatively simple systems, understanding protein–ligand association is challenging.

(Published Online July 3 2006)


Correspondence:
c1 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. Tel.: +1 617 495 9430; Fax: +1 617 495 9857; E-mail: gwhitesides@gmwgroup.harvard.edu