Systematic Investigation of Dual-Target-Directed Ligands.

Abstract

Multitarget-directed ligands (MTDLs) are compounds rationally designed to affect multiple targets, aiming for a better therapeutic profile. For over 20 years, MTDLs have garnered increasing attention, the idea being that their full potential would have been achieved, thanks to unprecedented target combinations and advanced medicinal chemistry strategies. This study presents a literature mining effort resulting in a data set of dual-target-directed ligands (DTDLs), the fundamental example of MTDLs. We used this data set to evaluate the rationale behind target selection and the chemical novelty of DTDLs targeting specific protein combinations. Our analysis focused on DTDL targets in terms of biological function, disease association, structure, and chemogenomic traits. We also compared DTDLs with single-target compounds. We found that well-known target pathology associations often guide DTDL design, leveraging existing chemical scaffolds and binding pocket similarities. These findings highlight the current state of the field and suggest substantial untapped potential for rational polypharmacology.