Pharmacophore modeling, drug design and virtual screening on multi-targeting procognitive agents approaching histaminergic pathways
Samo za registrovane korisnike
2015
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
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.
Ključne reči:
Drug design / 3D-QSAR / Histamine H-3 receptor / Histamine N-methyltransferase / Pharmacophore / Virtual screeningIzvor:
Journal of the Taiwan Institute of Chemical Engineers, 2015, 46, 15-29Izdavač:
- Elsevier Science BV, Amsterdam
Finansiranje / projekti:
- Sinteza, kvantitativni odnos između strukture i dejstva, fizičko-hemijska karakterizacija i analiza farmakološki aktivnih supstanci (RS-172033)
- Translational Research Innovation-Pharma (TRIP)
- Else Kroner-Fresenius-Stiftung
DOI: 10.1016/j.jtice.2014.09.017
ISSN: 1876-1070
WoS: 000348959600002
Scopus: 2-s2.0-84920375608
Institucija/grupa
PharmacyTY - JOUR AU - Nikolić, Katarina AU - Agbaba, Danica AU - Stark, Holger PY - 2015 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2402 AB - 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. PB - Elsevier Science BV, Amsterdam T2 - Journal of the Taiwan Institute of Chemical Engineers T1 - Pharmacophore modeling, drug design and virtual screening on multi-targeting procognitive agents approaching histaminergic pathways VL - 46 SP - 15 EP - 29 DO - 10.1016/j.jtice.2014.09.017 ER -
@article{ author = "Nikolić, Katarina and Agbaba, Danica and Stark, Holger", year = "2015", 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.", publisher = "Elsevier Science BV, Amsterdam", journal = "Journal of the Taiwan Institute of Chemical Engineers", title = "Pharmacophore modeling, drug design and virtual screening on multi-targeting procognitive agents approaching histaminergic pathways", volume = "46", pages = "15-29", doi = "10.1016/j.jtice.2014.09.017" }
Nikolić, K., Agbaba, D.,& Stark, H.. (2015). Pharmacophore modeling, drug design and virtual screening on multi-targeting procognitive agents approaching histaminergic pathways. in Journal of the Taiwan Institute of Chemical Engineers Elsevier Science BV, Amsterdam., 46, 15-29. https://doi.org/10.1016/j.jtice.2014.09.017
Nikolić K, Agbaba D, Stark H. Pharmacophore modeling, drug design and virtual screening on multi-targeting procognitive agents approaching histaminergic pathways. in Journal of the Taiwan Institute of Chemical Engineers. 2015;46:15-29. doi:10.1016/j.jtice.2014.09.017 .
Nikolić, Katarina, Agbaba, Danica, Stark, Holger, "Pharmacophore modeling, drug design and virtual screening on multi-targeting procognitive agents approaching histaminergic pathways" in Journal of the Taiwan Institute of Chemical Engineers, 46 (2015):15-29, https://doi.org/10.1016/j.jtice.2014.09.017 . .