Mapping Water Thermodynamics on Drug Candidates via Molecular Building Blocks: a Strategy to Improve Ligand Design and Rationalize SAR.
J Med Chem
; 64(8): 4662-4676, 2021 04 22.
Article
en En
| MEDLINE
| ID: mdl-33797902
ABSTRACT
The consideration of interactions involving water molecules in protein-ligand binding is widely appreciated in drug discovery nowadays. However, it is not ultimately clear how insights about these interactions translate into molecular design concepts. In this work, we introduce a computational strategy that, trained with high-precision experimental data, allows for the decomposition of water-related thermodynamic properties into chemically relevant building blocks (BBs) of a given ligand scaffold. For each of these BBs, a score based on solvation energy and entropy is computed, thus enabling the analysis of solvent-related affinity contributions for individual BBs. We find the nonvariable BB in a congeneric ligand pair to have a larger impact on the binding affinity than the variable part thus suggesting strong cooperative effects. Furthermore, we find enhanced solute-solvent interactions for a BB due to the presence of a C-F bond. Our investigation may be used to design drug molecules with tailored solvent thermodynamic properties.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
/
Proteínas
/
Ligandos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Alemania