Molecular modeling based approach, synthesis and in vitro assay to new indole inhibitors of hepatitis C NS3/4A serine protease

Ismail, Nasser S. M.; Hattori, Masao

doi:10.1016/j.bmc.2010.11.017

Cited by 14 publications

(10 citation statements)

References 28 publications

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“…PLA and PCL with twenty-five repeating units were reconstructed in an orthorhombic cell of dimension 36Å × 36Å × 18.8Å and 36Å × 36Å × 18.2Å, respectively. [25,26]. e results were presented in two types: (1) the binding site of the targeted protein for docking is specified.…”

Section: Molecular Modelingmentioning

confidence: 99%

Preparation and Characterization of MUC-30-Loaded Polymeric Micelles against MCF-7 Cell Lines Using Molecular Docking Methods and In Vitro Study

Nasongkla

Tuchinda

Munyoo

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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MUC-30 is a hydrophobic compound which is active against the MCF-7 cancer cell line. In this study, MUC-30 was loaded in polymeric micelles to improve the water solubility and release rate. For prolonged MUC-30 release, MUC-30 was encapsulated in polymeric micelles using PEG-b-PLA and PEG-b-PCL as materials. Micelles prepared with 1 : 9 w per w ratios by film hydration achieved the highest entrapment efficiency (EE%). The EE% of MUC-30-loaded PEG-b-PCL micelles was approximately 30% greater than that of PEG-b-PLA micelles, due to the different H-bond formations between MUC-30 and the polymer membrane (PCL, 4; PLA, 3). The cytotoxic activity of MUC-30 against EGFR theoretically presented 399.31 nM (IC50 = 282.26 ng/mL) by molecular docking. In vitro cytotoxic activity of MUC-30 was confirmed by MTT assay. MUC-30 (IC50 = 11 ± 0.39 ng/mL) showed three-fold higher activity over MUC-30-loaded PEG-b-PLA micelles (IC50 = 37 ± 1.18 ng/mL) and two-fold higher over PEG-b-PCL micelles (IC50 = 75 ± 3.97 ng/mL). This was due to the higher release rate of MUC-30 from PEG-b-PLA micelles compared to PEG-b-PCL micelles. Therefore, MUC-30-loaded PEG-b-PLA micelles could be a promising candidate for breast cancer chemotherapy.

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Section: Molecular Modelingmentioning

confidence: 99%

Preparation and Characterization of MUC-30-Loaded Polymeric Micelles against MCF-7 Cell Lines Using Molecular Docking Methods and In Vitro Study

Nasongkla

Tuchinda

Munyoo

et al. 2021

Evidence-Based Complementary and Alternative Medicine

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“…The crystal structure of the enzyme and erlotinib (1M17) 8 (Scheme 3) was obtained from protein data bank PDB 60 since erlotinib mimics ATP and binds to the ATP binding region of the kinase active site. Therefore, the synthesized compounds 2-5 were modelled by positioning them in the erlotinib binding site 61 .…”

Section: Molecular Modelling Study Of Egfr Inhibitor and Binding Confmentioning

confidence: 99%

Molecular modeling study bioactive natural product of khellin analogues as a novel potential pharmacophore of EGFR inhibitors

Elgazwy

Edrees

Ismail

2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…HCV infection has been declared as a principal health problem in more than 200 million individuals throughout the world [1] . It is a positive-stranded RNA virus and classified as a hepacivirus of the flaviviridae family [2] . Unlike other viral infections Hepatitis C Virus even with its high replication rate can stick within a human host for decades without any irritation or liver damage [3] .…”

Section: Introductionmentioning

confidence: 99%

In Silico Identification and Evaluation of Leads for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease Using Complex Based Pharmacophore Mapping and Virtual Screening

et al. 2014

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Hepatitis C virus (HCV) infection is an alarming and growing threat to public health. The present treatment gives limited efficacy and is poorly tolerated, recommending the urgent medical demand for novel therapeutics. NS3/4A protease is a significant emerging target for the treatment of HCV infection. This work reports the complex-based pharmacophore modeling to find out the important pharmacophoric features essential for the inhibition of both protease and helicase activity of NS3/4A protein of HCV. A seven featured pharmacophore model of HCV NS3/4A protease was developed from the crystal structure of NS3/4A protease in complex with a macrocyclic inhibitor interacting with both protease and helicase sites residues via MOE pharmacophore constructing tool. It consists of four hydrogen bond acceptors (Acc), one hydrophobic (Hyd), one for lone pair or active hydrogen (Atom L) and a heavy atom feature (Atom Q). The generated pharmacophore model was validated by a test database of seventy known inhibitors containing 55 active and 15 inactive/least active compounds. The validated pharmacophore model was used to virtually screen the ChemBridge database. As a result of screening 1009 hits were retrieved and were subjected to filtering by Lipinski’s rule of five on the basis of which 786 hits were selected for further assessment using molecular docking studies. Finally, 15 hits of different scaffolds having interactions with important active site residues were predicted as lead candidates. These candidates having unique scaffolds have a strong likelihood to act as further starting points in the development of novel and potent NS3/4A protease inhibitors.

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Molecular modeling based approach, synthesis and in vitro assay to new indole inhibitors of hepatitis C NS3/4A serine protease

Cited by 14 publications

References 28 publications

Preparation and Characterization of MUC-30-Loaded Polymeric Micelles against MCF-7 Cell Lines Using Molecular Docking Methods and In Vitro Study

Preparation and Characterization of MUC-30-Loaded Polymeric Micelles against MCF-7 Cell Lines Using Molecular Docking Methods and In Vitro Study

Molecular modeling study bioactive natural product of khellin analogues as a novel potential pharmacophore of EGFR inhibitors

In Silico Identification and Evaluation of Leads for the Simultaneous Inhibition of Protease and Helicase Activities of HCV NS3/4A Protease Using Complex Based Pharmacophore Mapping and Virtual Screening

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