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Kurczab R.,Polish Academy of Sciences | Nowak M.,Polish Academy of Sciences | Chilmonczyk Z.,Polish National Medicines Institute | Chilmonczyk Z.,University of Rzeszow | And 2 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

In an attempt to identify new ligands for the 5-HT7 receptor (5-HT7R), we developed and tested a hierarchical multi-step strategy of virtual screening (VS) based on two-dimensional (2D) pharmacophore similarity, physicochemical scalar descriptors, an ADME/Tox filter, three-dimensional (3D) pharmacophore searches and a docking protocol. Six chemical classes of 5-HT7R antagonists were used as query structures in a double-path virtual screening scheme. The Enamine screening database, consisting of approximately 730,000 commercially available drug-like compounds, was adopted and used as a source of structures. A biological evaluation of 26 finally selected virtual hits resulted in finding two benzodioxane derivatives with significant affinity (Ki = 197 and 265 nM). The approach described in this case study can be easily used as a general rational drug design tool for other biological targets. © 2010 Elsevier Ltd. All rights reserved. Source


Khan M.T.H.,Medical Pharmacology and Toxicology | Khan R.,Abdul Wali Khan University Mardan | Wuxiuer Y.,Medical Pharmacology and Toxicology | Arfan M.,University of Peshawar | And 2 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

A combinatorial series of novel quinazolin-4(3H)-ones were synthesised and their structures were established based on spectroscopic data (IR, NMR, EI-MS, and FAB-MS). The compounds were tested for inhibition of the zinc metalloproteinase thermolysin (TLN) utilizing a chemical array-based approach. Some of the compounds were found to inhibit TLN, with IC50 values ranging from 0.0115 μM (compound 3) to 122,637 μM (compound 29). Compound 3 [3-phenyl-2-(trifluoromethyl) quinazolin-4(3H)-one] (IC50 = 0.0115 μM) and compound 35 [3-(isopropylideneamino)-2,2-dimethyl-2,3-dihydroquinazolin-4 (1H)-one] (IC50 = 0.2477 μM) were found to be the most potent inhibitors. © 2010 Elsevier Ltd. All rights reserved. Source


Gabrielsen M.,Medical Pharmacology and Toxicology | Westrheim Ravna A.,Medical Pharmacology and Toxicology | Kristiansen K.,Medical Pharmacology and Toxicology | Sylte I.,Medical Pharmacology and Toxicology
Journal of Molecular Modeling | Year: 2012

The serotonin (5-HT) transporter (SERT) plays an important role in the termination of 5-HT-mediated neurotransmission by transporting 5-HT away from the synaptic cleft and into the presynaptic neuron. In addition, SERT is the main target for antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs). The three-dimensional (3D) structure of SERT has not yet been determined, and little is known about the molecular mechanisms of substrate binding and transport, though such information is very important for the development of new antidepressant drugs. In this study, a homology model of SERT was constructed based on the 3D structure of a prokaryotic homologous leucine transporter (LeuT) (PDB id: 2A65). Eleven tryptamine derivates (including 5-HT) and the SSRI (S)-citalopram were docked into the putative substrate binding site, and two possible binding modes of the ligands were found. To study the conformational effect that ligand binding may have on SERT, two SERT-5-HT and two SERT-(S)-citalopram complexes, as well as the SERT apo structure, were embedded in POPC lipid bilayers and comparative molecular dynamics (MD) simulations were performed. Our results show that 5-HT in the SERT- 5-HT B complex induced larger conformational changes in the cytoplasmic parts of the transmembrane helices of SERT than any of the other ligands. Based on these results, we suggest that the formation and breakage of ionic interactions with amino acids in transmembrane helices 6 and 8 and intracellular loop 1 may be of importance for substrate translocation. © Springer-Verlag 2011. Source

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