Novel family of fused tricyclic [1,4]diazepines: Design, synthesis, crystal structures and molecular docking studies

Adamski, Ariel; Kruszka, Dariusz; Dutkiewicz, Zbigniew; Kubicki, Maciej; Gorczyński, Adam; Patroniak, Violetta

doi:10.1016/j.tet.2017.05.015

Cited by 15 publications

(7 citation statements)

References 55 publications

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“…Drosophila melanogaster dopamine transporter (dDAT) is a proven model of DAT, which is 50% similar to mammalian DAT sequence, and is used in research into the mechanism of action of many compounds. Thus, in our docking studies we made use of the X-ray structure of dDAT in complex with the tricycilcanitide-pressant nortriptyline, which indicate primary binding site (PDB code: 4M48) [16].…”

Section: Methodsmentioning

confidence: 99%

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Study of novel triazolo-benzodiazepine analogues as antidepressants targeting by molecular docking and ADMET properties prediction

Belhassan

Zaki

Benlyas³

et al. 2019

Heliyon

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In this study, we have selected a series of a new family of molecules bearing Triazolo-benzodiazepines, an eleven membered heterocyclic ring has been studied for antidepression activity. Docking studies suggested that all the eleven ligands interacted well within active site of Drosophila melanogaster dopamine transporter (dDAT) (PDB ID: 4M48). Most ligands formed H-bond with amino acid Phe43, Asp46, Asp475, Tyr123, Ser421 and/or Gln316 and also exhibited Pi and Pi-Pi interactions with amino acid residues Tyr124, Phe319, Phe43, Phe325, Ala479 and Val120. In silico ADME evaluations of compounds showed more than 96% intestinal absorption for all compounds. During in vitro Toxicity properties prediction, the Triazolo-benzodiazepines derivatives: M1, M2, M3 and M11 showed less toxicity than the other studied molecules against algae, for daphnia the molecules M1, M2, M3, M8, M10 and M11 showed less toxicity than the reference molecule (Nortriptyline).

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Section: Methodsmentioning

confidence: 99%

“…Molecular docking turns out to be a reliable method for preliminary evaluation of binding affinity and prediction of intermolecular interactions of novel compounds with receptors [16]. Nowadays, this method has become indispensable for studying protein-ligand interactions.…”

Section: Introductionmentioning

confidence: 99%

Study of novel triazolo-benzodiazepine analogues as antidepressants targeting by molecular docking and ADMET properties prediction

Belhassan

Zaki

Benlyas³

et al. 2019

Heliyon

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“…Molecular docking results are focused on the dopamine transporter (DAT) bound to the tricyclic antidepressant nortriptyline, as a transmembrane protein that removes the neurotransmitter dopamine from the synaptic cleft and transports it into the cytosol of surrounding cells. The crystal structure of this receptor is extracted using the X-ray diffraction method at a resolution of 2.96 Å taken from the protein data base (PDB) [34][35][36]. In this part of the research, the molecular docking process is started for the following most active molecules (L6, L9, L30, L31 and L37) to predict the type of Intermolecular interactions established with the protein encoded 4M48, compared to the established interactions with the co-crystallized ligand (nortriptyline) pictured in Figure 7, which indicate that Phe43A, Phe325A and Tyr124A amino acids, are the active sites of the target protein, as sourced using the ProteinsPlus online server [37].…”

Section: Molecular Dockingmentioning

confidence: 99%

QSAR, ADMET In Silico Pharmacokinetics, Molecular Docking and Molecular Dynamics Studies of Novel Bicyclo (Aryl Methyl) Benzamides as Potent GlyT1 Inhibitors for the Treatment of Schizophrenia

et al. 2022

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Forty-four bicyclo ((aryl) methyl) benzamides, acting as glycine transporter type 1 (GlyT1) inhibitors, are developed using molecular modeling techniques. QSAR models generated by multiple linear and non-linear regressions affirm that the biological inhibitory activity against the schizophrenia disease is strongly and significantly correlated with physicochemical, geometrical and topological descriptors, in particular: Hydrogen bond donor, polarizability, surface tension, stretch and torsion energies and topological diameter. According to in silico ADMET properties, the most active ligands (L6, L9, L30, L31 and L37) are the molecules having the highest probability of penetrating the central nervous system (CNS), but the molecule 32 has the highest probability of being absorbed by the gastrointestinal tract. Molecular docking results indicate that Tyr124, Phe43, Phe325, Asp46, Phe319 and Val120 amino acids are the active sites of the dopamine transporter (DAT) membrane protein, in which the most active ligands can inhibit the glycine transporter type 1 (GlyT1). The results of molecular dynamics (MD) simulation revealed that all five inhibitors remained stable in the active sites of the DAT protein during 100 ns, demonstrating their promising role as candidate drugs for the treatment of schizophrenia.

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“…Owing to our experience in the construction of the imine-scaffolded metallosupramolecular architectures [29,30,31,32,33,34,35,36,37] and bioassays [30,36,38,39,40], we designed and synthesized a small library of Schiff base ligands (Scheme 1), where the main structural difference involves the different number and disposition of the hydrogen bond donors.…”

Section: Introductionmentioning

confidence: 99%

New Artificial Biomimetic Enzyme Analogues Based on Iron(II/III) Schiff Base Complexes: An Effect of (Benz)imidazole Organic Moieties on Phenoxazinone Synthase and DNA Recognition ‡

et al. 2019

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Elucidation of the structure and function of biomolecules provides us knowledge that can be transferred into the generation of new materials and eventually applications in e.g., catalysis or bioassays. The main problems, however, concern the complexity of the natural systems and their limited availability, which necessitates utilization of simple biomimetic analogues that are, to a certain degree, similar in terms of structure and thus behaviour. We have, therefore, devised a small library of six tridentate N-heterocyclic coordinating agents (L1–L6), which, upon complexation, form two groups of artificial, monometallic non-heme iron species. Utilization of iron(III) chloride leads to the formation of the 1:1 (Fe:Ln) ‘open’ complexes, whereas iron(II) trifluoromethanosulfonate allows for the synthesis of 1:2 (M:Ln) ‘closed’ systems. The structural differences between the individual complexes are a result of the information encoded within the metallic centre and the chosen counterion, whereas the organic scaffold influences the observed properties. Indeed, the number and nature of the external hydrogen bond donors coming from the presence of (benz)imidazole moieties in the ligand framework are responsible for the observed biological behaviour in terms of mimicking phenoxazinone synthase activity and interaction with DNA.

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Novel family of fused tricyclic [1,4]diazepines: Design, synthesis, crystal structures and molecular docking studies

Cited by 15 publications

References 55 publications

Study of novel triazolo-benzodiazepine analogues as antidepressants targeting by molecular docking and ADMET properties prediction

Study of novel triazolo-benzodiazepine analogues as antidepressants targeting by molecular docking and ADMET properties prediction

QSAR, ADMET In Silico Pharmacokinetics, Molecular Docking and Molecular Dynamics Studies of Novel Bicyclo (Aryl Methyl) Benzamides as Potent GlyT1 Inhibitors for the Treatment of Schizophrenia

New Artificial Biomimetic Enzyme Analogues Based on Iron(II/III) Schiff Base Complexes: An Effect of (Benz)imidazole Organic Moieties on Phenoxazinone Synthase and DNA Recognition ‡

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