Absolute binding free energy calculations improve enrichment of actives in virtual compound screening.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
10 08 2022
10 08 2022
Historique:
received:
10
05
2022
accepted:
26
07
2022
entrez:
10
8
2022
pubmed:
11
8
2022
medline:
13
8
2022
Statut:
epublish
Résumé
We determined the effectiveness of absolute binding free energy (ABFE) calculations to refine the selection of active compounds in virtual compound screening, a setting where the more commonly used relative binding free energy approach is not readily applicable. To do this, we conducted baseline docking calculations of structurally diverse compounds in the DUD-E database for three targets, BACE1, CDK2 and thrombin, followed by ABFE calculations for compounds with high docking scores. The docking calculations alone achieved solid enrichment of active compounds over decoys. Encouragingly, the ABFE calculations then improved on this baseline. Analysis of the results emphasizes the importance of establishing high quality ligand poses as starting points for ABFE calculations, a nontrivial goal when processing a library of diverse compounds without informative co-crystal structures. Overall, our results suggest that ABFE calculations can play a valuable role in the drug discovery process.
Identifiants
pubmed: 35948614
doi: 10.1038/s41598-022-17480-w
pii: 10.1038/s41598-022-17480-w
pmc: PMC9365818
doi:
Substances chimiques
Ligands
0
Amyloid Precursor Protein Secretases
EC 3.4.-
Aspartic Acid Endopeptidases
EC 3.4.23.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
13640Subventions
Organisme : NIGMS NIH HHS
ID : R01GM061300
Pays : United States
Informations de copyright
© 2022. The Author(s).
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