Are molecular fingerprints useful when seeking diverse active drugs? (no)

Computational approaches for small-molecule drug discovery now regularly scale to consideration of libraries containing billions of candidate small molecules. One promising approach to increased speed in evaluating billion-molecule libraries is to develop succinct representations of each molecule that enable rapid identification of molecules with similar properties. Molecular fingerprints are thought to provide a mechanism for producing such representations. Here, we explore the utility of commonly-used fingerprints in the context of predicting similar molecular activity. We show that fingerprint similarity provides little discriminative power between active and inactive molecules for a target protein based on a known active. We also demonstrate that, even when limited to only active molecules, fingerprint similarity values do not correlate with compound potency. In sum, these results highlight the need for a new wave of molecular representations that will improve the capacity to detect biologically active molecules based on similarity to other such molecules.. ### Competing Interest Statement The authors have declared no competing interest. * (TT) : Topological torsion (ECFP) : Extended Connectivity Fingerprint (FCFP) : Functional Class Fingerprint (AP2D) : Atom pair (AT2D) : Atom Triplet (ASP) : All Star Paths (DFS) : Depth First Search