ePharmaLib: A Versatile Library of e‑Pharmacophores to Address Small-Molecule (Poly-)Pharmacology

Bioactive compounds
oftentimes bind to several target proteins,
thereby exhibiting polypharmacology. Experimentally determining these
interactions is however laborious, and structure-based virtual screening
(SBVS) of bioactive compounds could expedite drug discovery by prioritizing
hits for experimental validation. Here, we present ePharmaLib, a library
of 15,148 e-pharmacophores modeled from solved structures of pharmaceutically
relevant protein–ligand complexes of the screening Protein
Data Bank (sc-PDB). ePharmaLib can be used for target fishing of phenotypic
hits, side effect predictions, drug repurposing, and scaffold hopping.
In retrospective SBVS, a good balance was obtained between computational
efficiency and predictive accuracy. As a proof of concept, we carried
out prospective SBVS in conjunction with a photometric assay, which
inferred that the mechanism of action of neopterin (an endogenous
immunomodulator) putatively stems from its inhibition (IC50 = 18 μM) of the human purine nucleoside phosphorylase. This
ready-to-use library is freely available at http://www.pharmbioinf.uni-freiburg.de/epharmalib.