Comparative evaluation of 3D virtual ligand screening methods: impact of the molecular alignment on enrichment.
J Chem Inf Model
; 50(6): 992-1004, 2010 Jun 28.
Article
en En
| MEDLINE
| ID: mdl-20527883
ABSTRACT
In the early stage of drug discovery programs, when the structure of a complex involving a target and a small molecule is available, structure-based virtual ligand screening methods are generally preferred. However, ligand-based strategies like shape-similarity search methods can also be applied. Shape-similarity search methods consist in exploring a pseudo-binding-site derived from the known small molecule used as a reference. Several of these methods use conformational sampling algorithms which are also shared by corresponding docking methods:
for example Surflex-dock/Surflex-sim, FlexX/FlexS, ICM, and OMEGA-FRED/OMEGA-ROCS. Using 11 systems issued from the challenging "own" subsets of the Directory of Useful Decoys (DUD-own), we evaluated and compared the performance of the above-cited programs in terms of molecular alignment accuracy, enrichment in active compounds, and enrichment in different chemotypes (scaffold-hopping). Since molecular alignment is a crucial aspect of performance for the different methods, we have assessed its impact on enrichment. We have also illustrated the paradox of retrieving active compounds with good scores even if they are inaccurately positioned. Finally, we have highlighted possible positive aspects of using shape-based approaches in drug-discovery protocols when the structure of the target in complex with a small molecule is known.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Interfaz Usuario-Computador
/
Evaluación Preclínica de Medicamentos
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Idioma:
En
Revista:
J Chem Inf Model
Asunto de la revista:
INFORMATICA MEDICA
/
QUIMICA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Francia