Protein-Based Virtual Screening Tools Applied for RNA-Ligand Docking Identify New Binders of the preQ1-Riboswitch.
J Chem Inf Model
; 62(17): 4134-4148, 2022 09 12.
Article
em En
| MEDLINE
| ID: mdl-35994617
ABSTRACT
Targeting RNA with small molecules is an emerging field. While several ligands for different RNA targets are reported, structure-based virtual screenings (VSs) against RNAs are still rare. Here, we elucidated the general capabilities of protein-based docking programs to reproduce native binding modes of small-molecule RNA ligands and to discriminate known binders from decoys by the scoring function. The programs were found to perform similar compared to the RNA-based docking tool rDOCK, and the challenges faced during docking, namely, protomer and tautomer selection, target dynamics, and explicit solvent, do not largely differ from challenges in conventional protein-ligand docking. A prospective VS with the Bacillus subtilis preQ1-riboswitch aptamer domain performed with FRED, HYBRID, and FlexX followed by microscale thermophoresis assays identified six active compounds out of 23 tested VS hits with potencies between 29.5 nM and 11.0 µM. The hits were selected not solely based on their docking score but for resembling key interactions of the native ligand. Therefore, this study demonstrates the general feasibility to perform structure-based VSs against RNA targets, while at the same time it highlights pitfalls and their potential solutions when executing RNA-ligand docking.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Riboswitch
Tipo de estudo:
Diagnostic_studies
/
Observational_studies
/
Prognostic_studies
/
Screening_studies
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article