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Pharmacophore modeling, drug design and virtual screening on multi-targeting procognitive agents approaching histaminergic pathways
dc.creator | Nikolić, Katarina | |
dc.creator | Agbaba, Danica | |
dc.creator | Stark, Holger | |
dc.date.accessioned | 2019-09-02T11:47:01Z | |
dc.date.available | 2019-09-02T11:47:01Z | |
dc.date.issued | 2015 | |
dc.identifier.issn | 1876-1070 | |
dc.identifier.uri | https://farfar.pharmacy.bg.ac.rs/handle/123456789/2402 | |
dc.description.abstract | 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. | en |
dc.publisher | Elsevier Science BV, Amsterdam | |
dc.relation | info:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172033/RS// | |
dc.relation | Translational Research Innovation-Pharma (TRIP) | |
dc.relation | Else Kroner-Fresenius-Stiftung | |
dc.rights | restrictedAccess | |
dc.source | Journal of the Taiwan Institute of Chemical Engineers | |
dc.subject | Drug design | en |
dc.subject | 3D-QSAR | en |
dc.subject | Histamine H-3 receptor | en |
dc.subject | Histamine N-methyltransferase | en |
dc.subject | Pharmacophore | en |
dc.subject | Virtual screening | en |
dc.title | Pharmacophore modeling, drug design and virtual screening on multi-targeting procognitive agents approaching histaminergic pathways | en |
dc.type | article | |
dc.rights.license | ARR | |
dcterms.abstract | Старк, Холгер; Николић, Катарина; Aгбаба, Даница; | |
dc.citation.volume | 46 | |
dc.citation.spage | 15 | |
dc.citation.epage | 29 | |
dc.citation.other | 46: 15-29 | |
dc.citation.rank | M21 | |
dc.identifier.wos | 000348959600002 | |
dc.identifier.doi | 10.1016/j.jtice.2014.09.017 | |
dc.identifier.scopus | 2-s2.0-84920375608 | |
dc.type.version | publishedVersion |