Water molecules in protein-ligand interfaces. Evaluation of software tools and SAR comparison.
J Comput Aided Mol Des
; 33(3): 307-330, 2019 03.
Article
en En
| MEDLINE
| ID: mdl-30756207
ABSTRACT
Targeting the interaction with or displacement of the 'right' water molecule can significantly increase inhibitor potency in structure-guided drug design. Multiple computational approaches exist to predict which waters should be targeted for displacement to achieve the largest gain in potency. However, the relative success of different methods remains underexplored. Here, we present a comparison of the ability of five water prediction programs (3D-RISM, SZMAP, WaterFLAP, WaterRank, and WaterMap) to predict crystallographic water locations, calculate their binding free energies, and to relate differences in these energies to observed changes in potency. The structural cohort included nine Bruton's Tyrosine Kinase (BTK) structures, and nine bromodomain structures. Each program accurately predicted the locations of most crystallographic water molecules. However, the predicted binding free energies correlated poorly with the observed changes in inhibitor potency when solvent atoms were displaced by chemical changes in closely related compounds.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Simulación por Computador
/
Agua
/
Modelos Moleculares
/
Inhibidores de Proteínas Quinasas
/
Agammaglobulinemia Tirosina Quinasa
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
J Comput Aided Mol Des
Asunto de la revista:
BIOLOGIA MOLECULAR
/
ENGENHARIA BIOMEDICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Alemania