scholarly journals Theoretical Investigation of the Structural, Spectroscopic, Electronic, and Pharmacological Properties of 4-Nerolidylcathecol, an Important Bioactive Molecule

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Renyer A. Costa ◽  
Earle Silva A. Junior ◽  
Jaqueline de A. Bezerra ◽  
Josiana Moreira Mar ◽  
Emerson S. Lima ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Energy Gap ◽  
Molecular Geometry ◽  
Competitive Inhibitor ◽  
Free Energies ◽  
Uv Spectrum ◽  
Dna Topoisomerase ◽  
Ir Studies ◽  
Docking Calculations ◽  
Dna Complex

4-Nerolidylcatechol (4NRC), a secondary metabolite described as a potent antioxidant that presents anti-inflammatory, antimalarial, analgesic, and cytotoxic properties, has been receiving prominence in the catechol class. In this work, a theoretical DFT study of the vibrational, structural, and quantum properties of 4-nerolidylcatechol (4NRC) using the B3LYP/6-311G (2d,p) level is presented. The theoretical molecular geometry data were compared with the X-ray data of a similar molecule in the associated literature and a conformational study is presented, with the aim of providing a good comprehension of the 4NRC structural arrangement and stability. Also, HOMO-LUMO energy gap and natural bond orbitals (NBOs) were performed and discussed. The calculated UV spectrum showed similarity to the experimentally obtained data, with transitions assigned. The comparative IR studies revealed that intermolecular hydrogen bonds that stabilize dimeric forms are plausible and also allowed the assignment of several characteristic vibrations. Molecular docking calculations with DNA topoisomerase I-DNA complex (TOPO-I), glyceraldehyde 3-phospate dehydrogenase (GAPDH), and Plasmodium falciparum lactate dehydrogenase (PfLDH) showed binding free energies of −6.3, −6.5, and −7.6 kcal/mol, respectively, which indicates that 4NRC is a good competitive inhibitor for these enzymes.

scholarly journals Purification and characterization of a proteolytic active fragment of DNA topoisomerase I from the brine shrimp Artemia franciscana (Crustacea Anostraca)

1992 ◽  
Vol 282 (1) ◽  
pp. 249-254 ◽  
Author(s):  
G Badaracco ◽  
N Landsberger ◽  
R Benfante
Keyword(s):  
Molecular Mass ◽  
Topoisomerase I ◽  
Specific Inhibitor ◽  
Artemia Franciscana ◽  
Type I ◽  
Bivalent Cation ◽  
Dna Topoisomerase ◽  
Proteolytic Fragment ◽  
Dna Complex

The ATP-independent type I topoisomerase from the crustacean Artemia franciscana was purified to near-homogeneity. Its activity was measured by an assay that uses the formation of an enzyme-cleaved DNA complex in the presence of the specific inhibitor camptothecin. The purification procedure is reported. Purified topoisomerase is a single-subunit enzyme with a molecular mass of 63 kDa. Immunoblot performed on the different steps of purification shows that the purified 63 kDa peptide is a proteolytic fragment of a protein with a molecular mass of 110 kDa. Similarly to the other purified eukaryotic topoisomerases, the crustacean enzyme does not require a bivalent cation for activity, but is stimulated in the presence of 10 mM-MgCl2; moreover, it can relax both negative and positive superhelical turns. The enzyme activity is strongly inhibited by the antitumour drug camptothecin. The enzyme inhibition is related to the stabilization of the cleavable complex between topoisomerase I and DNA.

scholarly journals Internalization of Foldamer-Based DNA Mimics through a Site-Specific Antibody Conjugate to Target HER2-Positive Cancer Cells

2021 ◽  
Vol 14 (7) ◽  
pp. 624
Author(s):  
Valentina Corvaglia ◽  
Imène Ait Mohamed Amar ◽  
Véronique Garambois ◽  
Stéphanie Letast ◽  
Aurélie Garcin ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Topoisomerase I ◽  
Ovarian Cancer Cells ◽  
Cellular Functions ◽  
Antibody Drug Conjugate ◽  
Her2 Positive ◽  
Dna Topoisomerase ◽  
Antibody Conjugate ◽  
A Site

Inhibition of protein–DNA interactions represents an attractive strategy to modulate essential cellular functions. We reported the synthesis of unique oligoamide-based foldamers that adopt single helical conformations and mimic the negatively charged phosphate moieties of B-DNA. These mimics alter the activity of DNA interacting enzymes used as targets for cancer treatment, such as DNA topoisomerase I, and they are cytotoxic only in the presence of a transfection agent. The aim of our study was to improve internalization and selective delivery of these highly charged molecules to cancer cells. For this purpose, we synthesized an antibody-drug conjugate (ADC) using a DNA mimic as a payload to specifically target cancer cells overexpressing HER2. We report the bioconjugation of a 16-mer DNA mimic with trastuzumab and its functional validation in breast and ovarian cancer cells expressing various levels of HER2. Binding of the ADC to HER2 increased with the expression of the receptor. The ADC was internalized into cells and was more efficient than trastuzumab at inhibiting their growth in vitro. These results provide proof of concept that it is possible to site-specifically graft high molecular weight payloads such as DNA mimics onto monoclonal antibodies to improve their selective internalization and delivery in cancer cells.

scholarly journals Mechanisms of camptothecin resistance in yeast DNA topoisomerase I mutants.

1993 ◽  
Vol 268 (30) ◽  
pp. 22322-22330
Author(s):  
A.M. Knab ◽  
J Fertala ◽  
M.A. Bjornsti
Keyword(s):  
Topoisomerase I ◽  
Dna Topoisomerase I ◽  
Dna Topoisomerase

scholarly journals In Vitro and In Silico Characterization of an Antimalarial Compound with Antitumor Activity Targeting Human DNA Topoisomerase IB

2021 ◽  
Vol 22 (14) ◽  
pp. 7455
Author(s):  
Bini Chhetri Soren ◽  
Jagadish Babu Dasari ◽  
Alessio Ottaviani ◽  
Beatrice Messina ◽  
Giada Andreotti ◽  
...  
Keyword(s):  
Enzyme Reaction ◽  
Dna Topoisomerase ◽  
Human Dna ◽  
Topoisomerase Ib ◽  
Topological State ◽  
Cleavage Step ◽  
Dynamics Simulations ◽  
In Silico Characterization ◽  
Dna Complex

Human DNA topoisomerase IB controls the topological state of supercoiled DNA through a complex catalytic cycle that consists of cleavage and religation reactions, allowing the progression of fundamental DNA metabolism. The catalytic steps of human DNA topoisomerase IB were analyzed in the presence of a drug, obtained by the open-access drug bank Medicines for Malaria Venture. The experiments indicate that the compound strongly and irreversibly inhibits the cleavage step of the enzyme reaction and reduces the cell viability of three different cancer cell lines. Molecular docking and molecular dynamics simulations suggest that the drug binds to the human DNA topoisomerase IB-DNA complex sitting inside the catalytic site of the enzyme, providing a molecular explanation for the cleavage-inhibition effect. For all these reasons, the aforementioned drug could be a possible lead compound for the development of an efficient anti-tumor molecule targeting human DNA topoisomerase IB.

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