Drug Target Identification Using Side-Effect Similarity

TLDR

Targets for drugs have traditionally been predicted using molecular or cellular features, such as chemical structure or cell‑line activity similarity. The study aims to determine whether phenotypic side‑effect similarities can predict shared drug targets. The authors used side‑effect similarity analysis to infer shared targets between drugs. Analysis of 746 marketed drugs revealed 1,018 side‑effect‑driven drug‑drug relationships, including 261 between chemically dissimilar drugs from different indications; experimental validation of 20 such pairs confirmed 13 target associations, 11 with sub‑10 µM inhibition constants, and nine were further supported by cell‑based assays, demonstrating the feasibility of phenotypic inference for drug‑target discovery and repurposing.

Abstract

Targets for drugs have so far been predicted on the basis of molecular or cellular features, for example, by exploiting similarity in chemical structure or in activity across cell lines. We used phenotypic side-effect similarities to infer whether two drugs share a target. Applied to 746 marketed drugs, a network of 1018 side effect-driven drug-drug relations became apparent, 261 of which are formed by chemically dissimilar drugs from different therapeutic indications. We experimentally tested 20 of these unexpected drug-drug relations and validated 13 implied drug-target relations by in vitro binding assays, of which 11 reveal inhibition constants equal to less than 10 micromolar. Nine of these were tested and confirmed in cell assays, documenting the feasibility of using phenotypic information to infer molecular interactions and hinting at new uses of marketed drugs.