Systematic Data Mining Reveals Synergistic H3R/MCHR1 Ligands

In this study, we
report a ligand-centric data mining approach
that guided the identification of suitable target profiles for treating
obesity. The newly developed method is based on identifying target
pairs for synergistic positive effects and also encompasses the exclusion
of compounds showing a detrimental effect on obesity treatment (off-targets).
Ligands with known activity against obesity-relevant targets were
compared using fingerprint representations. Similar compounds with
activities to different targets were evaluated for the mechanism of
action since activation or deactivation of drug targets determines
the pharmacological effect. In vitro validation of
the modeling results revealed that three known modulators of melanin-concentrating
hormone receptor 1 (MCHR1) show a previously unknown submicromolar
affinity to the histamine H3 receptor (H3R). This synergistic
activity may present a novel therapeutic option against obesity.