Methods for generating and applying pharmacophore models as virtual screening filters and for bioactivity profiling

•Pharmacophore models represent the 3D-arrangement of the chemical functionalities that make a molecule active towards its target.•Pharmacophore models are constructed either the ligand-based or the structure-based way.•Pharmacophore models are used for virtual screening, parallel screening, target fishing, and for SAR-studies.

Biological effects of small molecules in an organism result from favorable interactions between the molecules and their target proteins. These interactions depend on chemical functionalities, bonds, and their 3D-orientations towards each other. These 3D-arrangements of chemical functionalities that make a small molecule active towards its target can be described by pharmacophore models. In these models, chemical functionalities are represented as so-called features. Commonly, they are obtained either from a set of active compounds or directly from the observed protein–ligand interactions as present in X-ray crystal structures, NMR structures, or docking poses. In this review, we explain the basics of pharmacophore modeling including dataset generation, 3D-representations and conformational analysis of small molecules, pharmacophore model construction, model validation, and its benefits to virtual screening and other applications.

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