Entropic contribution to the linking coefficient in fragment based drug design: a case study

Valentina Borsi; Vito Calderone; Marco Fragai; Claudio Luchinat; Niko Sarti

doi:10.1021/jm901723z

Entropic contribution to the linking coefficient in fragment based drug design: a case study

J Med Chem. 2010 May 27;53(10):4285-9. doi: 10.1021/jm901723z.

Authors

Valentina Borsi¹, Vito Calderone, Marco Fragai, Claudio Luchinat, Niko Sarti

Affiliation

¹ Magnetic Resonance Center (CERM), University of Florence, Florence, Italy.

PMID: 20415416
DOI: 10.1021/jm901723z

Abstract

For several drug leads obtained by tethering weak binding ligands, the dissociation constant is smaller than the product of those of the individual fragments by a factor named the linking coefficient, E. This favorable contribution is attributed to the entropic gain that is realized when two weak binding ligands are tethered. Here we show a case study where the linking coefficient is strikingly small (E = 2.1 x 10(-3) M(-1)) and its totally entropic nature is demonstrated.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Calorimetry
Catalytic Domain
Crystallography, X-Ray
Drug Design*
Entropy*
Hydroxamic Acids / chemistry*
Ligands
Magnetic Resonance Spectroscopy
Matrix Metalloproteinase 12 / chemistry*
Matrix Metalloproteinase Inhibitors*
Models, Molecular
Protein Binding
Sulfonamides / chemistry*

Substances

Hydroxamic Acids
Ligands
Matrix Metalloproteinase Inhibitors
Sulfonamides
acetohydroxamic acid
Matrix Metalloproteinase 12