Systematic Investigation of Dual-Target-Directed Ligands

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.