Fighting High Molecular Weight in Bioactive Molecules with Sub-Pharmacophore-Based Virtual Screening

A new subpharmacophore-based virtual screening method
is introduced.
Subpharmacophores are derived from large active molecules to detect
small bioactive molecules as seeds for starting points in medicinal
chemistry programs. A large data set was assembled from the ChEMBL
database to check the validity of this approach. Molecules for 133
targets with molecular weights between 450 and 850 were selected as
queries. For the query molecules, the pharmacophore descriptors were
calculated. Up to 56 000 subpharmacophore descriptors with
five to seven pharmacophore points were derived from the query pharmacophores.
The subpharmacophore descriptors were used as queries to screen 1079
test data sets, containing decoys and spike molecules. A maximum upper
molecular weight limit of 400 Da was set for the test molecules. Three
different chemical fingerprint descriptors were used for comparison
purposes. The subpharmacophore approach detected active molecules
for 85 out of 133 targets and outperformed the chemical fingerprints.
This ligand-based virtual screening experiment was triggered by the
needs of medicinal chemistry. Applying the subpharmacophore method
in a medicinal chemistry program, where a lead molecule with a molecular
weight of 800 Da was available, resulted in a new series of molecules
with molecular weights below 400.