The importance of hydration thermodynamics in fragment-to-lead optimization.
ChemMedChem
; 9(12): 2708-17, 2014 Dec.
Article
em En
| MEDLINE
| ID: mdl-25164952
ABSTRACT
Using a computational approach to assess changes in solvation thermodynamics upon ligand binding, we investigated the effects of water molecules on the binding energetics of over 20 fragment hits and their corresponding optimized lead compounds. Binding activity and X-ray crystallographic data of published fragment-to-lead optimization studies from various therapeutically relevant targets were studied. The analysis reveals a distinct difference between the thermodynamic profile of water molecules displaced by fragment hits and those displaced by the corresponding optimized lead compounds. Specifically, fragment hits tend to displace water molecules with notably unfavorable excess entropies-configurationally constrained water molecules-relative to those displaced by the newly added moieties of the lead compound during the course of fragment-to-lead optimization. Herein we describe the details of this analysis with the goal of providing practical guidelines for exploiting thermodynamic signatures of binding site water molecules in the context of fragment-to-lead optimization.
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Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Água
/
Desenho de Fármacos
Tipo de estudo:
Guideline
Idioma:
En
Revista:
ChemMedChem
Assunto da revista:
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2014
Tipo de documento:
Article