Pharmacophore modeling, drug design and virtual screening on multi-targeting procognitive agents approaching histaminergic pathways

In an effort to design dual acting compounds enhancing histaminergic neurotransmission in the central nervous system, a novel class of 35 non-imidazole histamine H-3 receptor (H3R) antagonists that simultaneously possess strong inhibitory potency on catabolic histamine N-methyltransferase (HMT), have been examined by 3D-QSAR study. For improved understanding, the crucial chemical functionalities for combined H3R/HMT activities 3D-QSAR pharmacophore models (H3R: R-2 (0.98), Q(2)(0.94), RMSE (0.171); and HMT: R-2 (0.80), Q(2) (0.60), RMSE (0.159) were developed. Pharmacophore for H3R antagonistic activity mainly differs from pharmacophore for HMT inhibiting activity in presence of specific lipophilic/steric components of the H3R pharmacophore, H-bond accepting components of the H3R pharmacophore, H-bond donating components of the HMT pharmacophore, and longer optimal distance between H-bond donor and steric hot spots in the H3R pharmacophore than in the HMT pharmacophore. Formed 3D-QSAR models were applied for design of novel piperidino-aminoquinoline hybrids as multitarget H3R/HMT ligands with potential impact in therapy of sleep-wake disorders and cognitive impairment. Designed compounds with 3D-QSAR predicted pKi (H3R) > 9.6 and (pKi (H3R) + pIC(50)(HMT)) > 16.8 were selected for further profiling. Virtual screening of ZINC database is performed against the most promising H3R/HMT ligand and top ranked compounds are tested by both 3D-QSAR models. (C) 2014 Taiwan Institute of Chemical Engineers. Published by Elsevier B.V. All rights reserved.