Ligand efficiency based approach for efficient virtual screening of compound libraries

Eur J Med Chem. 2014 Aug 18:83:226-35. doi: 10.1016/j.ejmech.2014.06.029. Epub 2014 Jun 14.

Abstract

Here we report for the first time the use of fit quality (FQ), a ligand efficiency (LE) based measure for virtual screening (VS) of compound libraries. The LE based VS protocol was used to screen an in-house database of 125,000 compounds to identify aurora kinase A inhibitors. First, 20 known aurora kinase inhibitors were docked to aurora kinase A crystal structure (PDB ID: 2W1C); and the conformations of docked ligand were used to create a pharmacophore (PH) model. The PH model was used to screen the database compounds, and rank (PH rank) them based on the predicted IC50 values. Next, LE_Scale, a weight-dependant LE function, was derived from 294 known aurora kinase inhibitors. Using the fit quality (FQ = LE/LE_Scale) score derived from the LE_Scale function, the database compounds were reranked (PH_FQ rank) and the top 151 (0.12% of database) compounds were assessed for aurora kinase A inhibition biochemically. This VS protocol led to the identification of 7 novel hits, with compound 5 showing aurora kinase A IC50 = 1.29 μM. Furthermore, testing of 5 against a panel of 31 kinase reveals that it is selective toward aurora kinase A & B, with <50% inhibition for other kinases at 10 μM concentrations and is a suitable candidate for further development. Incorporation of FQ score in the VS protocol not only helped identify a novel aurora kinase inhibitor, 5, but also increased the hit rate of the VS protocol by improving the enrichment factor (EF) for FQ based screening (EF = 828), compared to PH based screening (EF = 237) alone. The LE based VS protocol disclosed here could be applied to other targets for hit identification in an efficient manner.

Keywords: Aurora kinase inhibitor; Fit quality; Ligand efficiency; Pharmacophore model; Virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase A / antagonists & inhibitors
  • Aurora Kinase A / chemistry
  • Aurora Kinase A / metabolism
  • Drug Evaluation, Preclinical / methods*
  • High-Throughput Screening Assays
  • Ligands
  • Molecular Docking Simulation
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / chemistry
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology
  • Pyrimidines / chemistry
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism
  • Small Molecule Libraries / pharmacology*
  • User-Computer Interface*

Substances

  • Ligands
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Small Molecule Libraries
  • Aurora Kinase A