Design, Synthesis, and Molecular-modeling Study of Aminothienopyridine Analogues of Tacrine for Alzheimer's Disease

2010 ◽  
Vol 343 (10) ◽  
pp. 590-601 ◽  
Author(s):  
Mohga M. Badran ◽  
Maha Abdel Hakeem ◽  
Suzan M. Abuel-Maaty ◽  
Afaf El-Malah ◽  
Rania M. Abdel Salam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Modeling ◽  
Design Synthesis ◽  
Molecular Modeling Study ◽  
Modeling Study

Proposition of Potential GSK-3β Inhibitors for the Treatment of Alzheimer’s Disease: A Molecular Modeling Study

2020 ◽  
Vol 16 (5) ◽  
pp. 541-554
Author(s):  
Leandro L. Castro ◽  
Leide C. S. Picanço ◽  
Jaderson V. Silva ◽  
Lucilene R. Souza ◽  
Kessia P. A. Sousa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Modeling ◽  
Glycogen Synthase ◽  
Template Molecule ◽  
Cell Degeneration ◽  
Carcinogenic Activity ◽  
Molecular Modeling Study ◽  
Gsk 3Β ◽  
Modeling Study

Introduction: The enzyme Glycogen Synthase Kinase 3-β (GSK-3β) is related to neuronal cell degeneration, representing a promising target to treat Alzheimer’s Disease (AD). Methods: In this work, we performed a molecular modeling study of existing GSK-3β inhibitors by means of evaluation of their IC50 values, derivation of a pharmacophore model, molecular docking simulations, ADME/Tox properties predictions, molecular modifications and prediction of synthetic viability. Results: In this manner, inhibitor 15 (CID 57399952) was elected a template molecule, since it demonstrated to bear relevant structural groups able to interact with GSK-3β, and also presented favorable ADME/Tox predicted properties, except for mutagenicity. Based on this inhibitor chemical structure we proposed six analogues that presented the absence of alerts for mutagenic and carcinogenic activity, both for rats and mouse; likewise they all presented low risk alerts for inhibition of hERG and medium prediction of synthetic viability. Conclusion: It is concluded that the analogues of GSK-3β inhibitors were optimized in relation to the toxicity endpoint of the template molecule, being, therefore, presented as novel and promising drug candidates for AD treatment.

ChemInform Abstract: Design, Synthesis, and Molecular-Modeling Study of Aminothienopyridine Analogues of Tacrine for Alzheimer′s Disease.

ChemInform ◽  
2011 ◽  
Vol 42 (9) ◽  
pp. no-no
Author(s):  
Mohga M. Badran ◽  
Maha Abdel Hakeem ◽  
Suzan M. Abuel-Maaty ◽  
Afaf El-Malah ◽  
Rania M. Abdel Salam
Keyword(s):  
Molecular Modeling ◽  
Design Synthesis ◽  
Molecular Modeling Study ◽  
Modeling Study

Design, synthesis, cytotoxicity, and molecular modeling study of 2,4,6-trisubstituted pyrimidines with anthranilate ester moiety

2019 ◽  
Vol 28 (4) ◽  
pp. 545-558 ◽  
Author(s):  
Kirill P. Cheremnykh ◽  
Victor A. Savelyev ◽  
Mikhail A. Pokrovskii ◽  
Dmitry S. Baev ◽  
Tatyana G. Tolstikova ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Design Synthesis ◽  
Molecular Modeling Study ◽  
Ester Moiety ◽  
Modeling Study

scholarly journals Design, Synthesis and Molecular Modeling Study of Conjugates of ADP and Morpholino Nucleosides as A Novel Class of Inhibitors of PARP-1, PARP-2 and PARP-3

2019 ◽  
Vol 21 (1) ◽  
pp. 214
Author(s):  
Yuliya V. Sherstyuk ◽  
Nikita V. Ivanisenko ◽  
Alexandra L. Zakharenko ◽  
Maria V. Sukhanova ◽  
Roman Y. Peshkov ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Binding Site ◽  
Rational Design ◽  
In Silico Analysis ◽  
Parp Inhibition ◽  
High Yield ◽  
Design Synthesis ◽  
Molecular Modeling Study ◽  
Parp 1 ◽  
Modeling Study

We report on the design, synthesis and molecular modeling study of conjugates of adenosine diphosphate (ADP) and morpholino nucleosides as potential selective inhibitors of poly(ADP-ribose)polymerases-1, 2 and 3. Sixteen dinucleoside pyrophosphates containing natural heterocyclic bases as well as 5-haloganeted pyrimidines, and mimicking a main substrate of these enzymes, nicotinamide adenine dinucleotide (NAD+)-molecule, have been synthesized in a high yield. Morpholino nucleosides have been tethered to the β-phosphate of ADP via a phosphoester or phosphoramide bond. Screening of the inhibiting properties of these derivatives on the autopoly(ADP-ribosyl)ation of PARP-1 and PARP-2 has shown that the effect depends upon the type of nucleobase as well as on the linkage between ADP and morpholino nucleoside. The 5-iodination of uracil and the introduction of the P–N bond in NAD+-mimetics have shown to increase inhibition properties. Structural modeling suggested that the P–N bond can stabilize the pyrophosphate group in active conformation due to the formation of an intramolecular hydrogen bond. The most active NAD+ analog against PARP-1 contained 5-iodouracil 2ʹ-aminomethylmorpholino nucleoside with IC50 126 ± 6 μM, while in the case of PARP-2 it was adenine 2ʹ-aminomethylmorpholino nucleoside (IC50 63 ± 10 μM). In silico analysis revealed that thymine and uracil-based NAD+ analogs were recognized as the NAD+-analog that targets the nicotinamide binding site. On the contrary, the adenine 2ʹ-aminomethylmorpholino nucleoside-based NAD+ analogs were predicted to identify as PAR-analogs that target the acceptor binding site of PARP-2, representing a novel molecular mechanism for selective PARP inhibition. This discovery opens a new avenue for the rational design of PARP-1/2 specific inhibitors.

Design, synthesis and molecular modeling study of iminodiacetyl monohydroxamic acid derivatives as MMP inhibitors

2006 ◽  
Vol 14 (22) ◽  
pp. 7539-7550 ◽  
Author(s):  
M. Amélia Santos ◽  
Sérgio M. Marques ◽  
Tiziano Tuccinardi ◽  
Paolo Carelli ◽  
Laura Panelli ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Design Synthesis ◽  
Mmp Inhibitors ◽  
Molecular Modeling Study ◽  
Modeling Study
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