Protein Interface Pharmacophore Mapping Tools for Small Molecule Protein: Protein Interaction Inhibitor Discovery

Arnout      Voet; Eleanor F.      Banwell; Kamlesh K.      Sahu; Jonathan G.      Heddle; Kam Y. J.      Zhang

Abstract

Protein:protein interactions are becoming increasingly significant as potential drug targets; however, the rational identification of small molecule inhibitors of such interactions remains a challenge. Pharmacophore modelling is a popular tool for virtual screening of compound libraries, and has previously been successfully applied to the discovery of enzymatic inhibitors. However, the application of pharmacophore modelling in the field of protein:protein interaction inhibitors has historically been considered more of a challenge and remains limited. In this review, we explore the interaction mimicry by known inhibitors that originate from in vitro screening, demonstrating the validity of pharmacophore mapping in the generation of queries for virtual screening. We discuss the pharmacophore mapping methods that have been successfully employed in the discovery of first-in-class inhibitors. These successful cases demonstrate the usefulness of a “tool kit” of diverse strategies for application across a range of situations depending on the available structural information.

Keywords: Drug discovery, Pharmacophore modelling, Protein:protein interaction (PPI), Small molecule protein:protein interaction inhibitor (SMPPII), Virtual screening.

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