Generation of hundreds of drug-like non-toxic sub-nanoMolar affinity children targeting antihistamine H1R cavities with high specificity have been predicted using DWBEL and ADV dockings. Many of the newly predicted compounds cross-docked the same H1R α-helices than second-generation antihistamines, but with ~ 1000-fold higher docking affinities and higher HR specificities. Favoring alternative solutions, these high number of candidates may constitute examples for further research and in vivo evaluation of their possible out-of-target effects in animal models. Combinatorial chemical synthesis and/or selected analogues may provide alternatives for experimental evaluations.