Small Molecules as Toll-like Receptor 4 Modulators Drug and In-House Computational Repurposing
Lucía Pérez-Regidor, Joan Guzman‐Caldentey, Nils Oberhauser, Carmen Punzón, Balázs Balogh, José R. Pedro, Eva Falomir, Alessandra Nurisso, Péter Mátyus, J. Carlos Menéndez, Belén de Andrés, Manuel Fresno, Sonsoles Martín‐Santamaría
Abstract
The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a “computer-aided drug repurposing” approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 approved drugs and drug-like molecules from commercial, public, and in-house academia chemical libraries and, after biological assays, identified several compounds with TLR4 antagonist activity. Our computational protocol showed to be a robust approach for the identification of hits with drug-like scaffolds as possible inhibitors of the TLR4 innate immune pathways. Our collaborative work broadens the chemical diversity for inspiration of new classes of TLR4 modulators.