Guided rational design with scaffold hopping leading to novel histamine H3 receptor ligands.

[Display omitted] • New scaffolds for histamine H3 receptor ligands. • High drug-likeness of newly designed compounds by computational methods. • Selection of ligands by toxicological and ADME screening in silico. • Synthesis and proof of concept with one ligand selected. • Combination of diverse computational methods to the design of novel compounds with new scaffolds. During the past decades, histamine H 3 receptors have received widespread attention in pharmaceutical research due to their involvement in pathophysiology of several diseases such as neurodegenerative disorders. In this context, blocking of these receptors is of paramount importance in progression of such diseases. In the current investigation, novel histamine H 3 receptor ligands were designed by exploiting scaffold-hopping drug-design strategy. We inspected the designed molecules in terms of ADME properties, drug-likeness, as well as toxicity profiles. Additionally molecular docking and dynamics simulation studies were performed to predict binding mode and binding free energy calculations, respectively. Among the designed structures, we selected compound d2 and its demethylated derivative as examples for synthesis and affinity measurement. In vitro binding assays of the synthesized molecules demonstrated that d2 has lower binding affinity (K i = 2.61 μM) in radioligand displacement assay to hH 3 R than that of demethylated form (K i = 12.53 μM). The newly designed compounds avoid of any toxicity predictors resulted from extended in silico and experimental studies, can offer another scaffold for histamine H 3 R antagonists for further structure–activity relationship studies. [ABSTRACT FROM AUTHOR]