Extension of anti-H1R allergy space candidates by computational co-evolution

Histamine is a physiological molecule that binds to four organ-dependent similar 3D-receptors (HR) signaling activation to diverse mammalian functions. Excessive histamine concentrations trigger IgE-dependent allergies, anaphylactic shocks, inflammation, blood vessel dilatation, neurotransmission alterations, heart arrhythmias and other undesirable effects. H1R antihistamines have been used during years to reduce histamine high levels. Some antihistamines, however induced out-of-target impacts such as brain somnolence, potassium-channel-dependent heart arrhythmias or other effects because of HRs cross-bindings. This work computationally explored new H1R docking molecules with predicted antihistamine activities by co-evolution. Rather than screening large molecular banks, natural evolution was mimicked starting from parent molecules from second-generation antihistaminic drugs. Thousands of children fitting H1R histamine cavities were generated predicting low-toxicities and sub-nanoMolar affinities. Restricted co-evolutions increased the specificity of hundreds of fitted-children by reducing ~1000-fold their HR crossdockings.