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

Abstract

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.

Keywords: 3D-structures; Bioactivity predictions; Conformational models; Pharmacophore modeling; Virtual screening.