Computational study on superparamagnetic hyperthermia with biocompatible SPIONs to destroy the cancer cells

AbstractComputational approaches have emerging role for designing potential inhibitors against topoisomerase 2 for treatment of cancer. TOP2A plays a key role in DNA replication before cell division and thus facilitates the growth of cells. This function of TOP2A can be suppressed by targeting with potential inhibitors in cancer cells to stop the uncontrolled cell division. Among potential inhibitors cryptolepine is more selective and has the ability to intercalate into DNA, effectively block TOP2A and cease cell division in cancer cells. However, cryptolepine is non-specific and have low affinity, therefore, a combinatorial library was designed and virtually screened for identification of its derivatives with greater TOP2A binding affinities.A combinatorial library of 31114 derivatives of cryptolepine was formed and the library was virtually screened by molecular docking to predict the molecular interactions between cryptolepine derivatives and TOP2A taking cryptolepine as standard. The overall screening and docking approach explored all the binding poses of cryptolepine for TOP2A to calculate binding energy. The compounds are given database number 8618, 907, 147, 16755, and 8186 scored lowest binding energies of −9.88kcal/mol, −9.76kcal/mol, −9.75kcal/mol, −9.73kcal/mol, and −9.72kcal/mol respectively and highest binding affinity while cryptolepine binding energy is −6.09kcal/mol. The good binding interactions of the derivatives showed that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of derivatives with different amino acid residues were also observed. A comprehensive understanding of the interactions of proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This Computational study suggests useful references to understand inhibition mechanisms that will help in the modification of TOP2A inhibitors.

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Novel Targeted Anti-Tumor Nanoparticles Developed from Folic Acid-Modified 2-Deoxyglucose

International Journal of Molecular Sciences ◽

10.3390/ijms20030697 ◽

2019 ◽

Vol 20 (3) ◽

pp. 697 ◽

Cited By ~ 2

Author(s):

Shaoming Jin ◽

Zhongyao Du ◽

Huiyuan Guo ◽

Hao Zhang ◽

Fazheng Ren ◽

...

Keyword(s):

Folic Acid ◽

Cell Viability ◽

Cancer Cells ◽

Water Solubility ◽

Computational Study ◽

Biological Effects ◽

Docking Simulation ◽

Nano Particles ◽

Cycle Arrest ◽

Nano Drug Delivery

The glucose analog, 2-deoxyglucose (2-DG), specifically inhibits glycolysis of cancer cells and interferes with the growth of cancer cells. However, the excellent water solubility of 2-DG makes it difficult to be concentrated in tumor cells. In this study, a targeted nano-pharmacosome was developed with folic acid-modified 2-DG (FA-2-DG) by using amino ethanol as a cleavable linker. FA-2-DG was able to self-assemble, forming nano-particles with diameters of 10–30 nm. The biological effects were evaluated with cell viability assays and flow cytometry analysis. Compared with a physical mixture of folic acid and 2-DG, FA-2-DG clearly reduced cell viability and resulted in cell cycle arrest. A computational study involving docking simulation suggested that FA-2-DG can dock into the same receptor as folic acid, thus confirming that the structural modification did not affect the targeting performance. The results indicated that the nano-pharmacosome consisting of FA-2-DG can be used for targeting in a nano-drug delivery system.

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Catalytic mechanism of the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2)

10.1101/2021.11.03.467155 ◽

2021 ◽

Author(s):

Li Na Zhao ◽

Philipp Kaldis

Keyword(s):

Cancer Cells ◽

Dehydrogenase Activity ◽

Catalytic Mechanism ◽

Computational Study ◽

Valence Bond ◽

Water Molecules ◽

Surrounding Water ◽

Proton Coupled Electron Transfer ◽

Methylenetetrahydrofolate Dehydrogenase ◽

Key Residues

Methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a new drug target that is expressed in cancer cells but not in normal adult cells, which provides an Achilles heel to selectively kill cancer cells. Despite the availability of crystal structures of MTHFD2 in the inhibitor- and cofactor-bound forms, key information is missing due to technical limitations, including (a) the location of absolutely required Mg2+ ion, and (b) the substrate-bound form of MTHFD2. Using homology modeling and simulation studies, we propose that two magnesium ions are present at the active site whereby (i) Arg233, Asp225, and two water molecules coordinate MgA, while MgA together with Arg233 stabilize the inorganic phosphate (Pi); (ii) Asp168 and three water molecules coordinate MgB, and MgB further stabilizes Pi by forming a hydrogen bond with two oxygens of Pi; (iii) Arg201 directly coordinates the Pi; and (iv) through three water-mediated interactions, Asp168 contributes to the positioning and stabilization of MgA, MgB and Pi. Our computational study at the empirical valence bond level allowed us to elucidate the detailed reaction mechanisms. We found that the dehydrogenase activity features a proton-coupled electron transfer with charge redistribution coupled to the reorganization of the surrounding water molecules which further facilitates the subsequent cyclohydrolase activity. The cyclohydrolase activity then drives the hydration of the imidazoline ring and the ring opening in a concerted way. Furthermore, we have uncovered that two key residues Ser197/Arg233 are key factors in determining the cofactor (NADP+/NAD+) preference of the dehydrogenase activity. Our work sheds new light on the structural and kinetic framework of MTHFD2, which will be helpful to design small molecule inhibitors that can be used for cancer therapy.

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Chitosan and chitosan/PEG nanoparticles loaded with indole-3-carbinol: Characterization, computational study and potential effect on human bladder cancer cells

Materials Science and Engineering C ◽

10.1016/j.msec.2021.112089 ◽

2021 ◽

pp. 112089

Author(s):

Micael Nunes Melo ◽

Fernanda Menezes Pereira ◽

Matheus Alves Rocha ◽

Jesica Gonçalves Ribeiro ◽

Alexander Junges ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Computational Study ◽

Potential Effect ◽

Human Bladder Cancer ◽

Human Bladder ◽

Bladder Cancer Cells ◽

Human Bladder Cancer Cells

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Combinatorial library design and virtual screening of cryptolepine derivatives against topoisomerase IIA by molecular docking and DFT studies

Physical Sciences Reviews ◽

10.1515/psr-2020-0124 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Maria ◽

Zahid Khan ◽

Aleksey E. Kuznetsov

Keyword(s):

Molecular Docking ◽

Cell Division ◽

Binding Energy ◽

Cancer Cells ◽

Anticancer Agents ◽

Combinatorial Library ◽

Computational Study ◽

Binding Energies ◽

Binding Affinities ◽

Potential Inhibitors

Abstract Various computational approaches have received ever-growing role in the design of potential inhibitors of the topoisomerase 2 (TOP2A) for cancer treatment. TOP2A plays a key role in the deoxyribonucleic acid (DNA) replication before cell division and thus facilitates the growth of cells. This TOP2A function can be suppressed by targeting it with potential inhibitors in cancer cells to terminate the uncontrolled cell division. Among potential inhibitors, cryptolepine has higher selectivity along with the ability to intercalate into DNA, effectively blocking TOP2A and ceasing cell division in cancer cells. However, this compound has drawbacks of being nonspecific and possessing relatively low affinity. Therefore, a combinatorial library of 31,114 cryptolepine derivatives was designed and virtually screened by molecular docking to predict the molecular interactions between the cryptolepine derivatives and TOP2A using cryptolepine as a standard. All the binding poses of cryptolepine derivatives for TOP2A were investigated to calculate binding energy. The compounds with the database numbers 8618, 907, 147, 16755, and 8186 scored the highest binding energies, −9.88, −9.76, −9.75, −9.73, and −9.72 kcal/mol, respectively, and the highest binding affinities while the cryptolepine binding energy is −6.09 kcal/mol. The strong binding interactions of these derivatives show that they can be used as potent TOP2A inhibitors and act as more effective anticancer agents than cryptolepine itself. The interactions of these derivatives with different amino acid residues were also observed and analyzed. A comprehensive understanding of the interactions of the proposed derivatives with TOP2A helped for searching more novel and potent drug-like molecules for anticancer therapy. This computational study suggests useful references to understand inhibition mechanisms that will help in the further modifications of TOP2A inhibitors. Moreover, the DFT study of the derivatives with the highest binding energies was performed, helping to further understand the binding affinities of these compounds.

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Computational study, synthesis and evaluation of active peptides derived from Parasporin-2 and spike protein from Alphacoronavirus against colon cancer cells

Bioscience Reports ◽

10.1042/bsr20211964 ◽

2021 ◽

Author(s):

Jenniffer Cruz ◽

Miguel Orlando Suárez-Barrera ◽

Paola Rondón-Villarreal ◽

Andrés Olarte-Diaz ◽

Fanny Guzmán ◽

...

Keyword(s):

Colon Cancer ◽

Anticancer Activity ◽

Cancer Cells ◽

Solid Phase ◽

Computational Study ◽

Human Cancer ◽

Spike Protein ◽

Colon Cancer Cells ◽

Peptide Fragments ◽

Native Peptide

Parasporin-2Aa1 (PS2Aa1) is a toxic protein of 37 KDa (30 KDa, activated form produced by proteolysis) that was shown to be cytotoxic against specific human cancer cells, although its mechanism of action has not been elucidated yet. In order to study the role of some native peptide fragments of proteins on anticancer activity, here we investigated the cytotoxic effect of peptide fragments from domain-1 of PS2Aa1 and one of the loops present in the binding region of the virus spike protein from Alphacoronavirus (HCoV-229E), the latter according to scientific reports, who showed interaction with the human APN (h-APN) receptor, evidence corroborated through computational simulations, and thus being possible active against colon cancer cells. Peptides namely P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa were synthesized using the Fmoc solid-phase synthesis and characterized by mass spectrometry (MS). Additionally, one region from loop 1 of HCoV-229E, Loop1-HCoV-229E, was also synthesized and characterized. The A4W-GGN5 anticancer peptide and 5-fluorouracil (5-FU) were taken as a control in all experiments. Circular dichroism revealed an α-helix structure for the peptides derived from PS2Aa1 (P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa) and β-laminar structure for the peptide derived from Alphacoronavirus spike protein Loop1-HCoV-229E. Peptides showed a hemolysis percentage of less than 20% at 100 µM concentration. Besides, peptides exhibited stronger anticancer activity against SW480 and SW620 cells after exposure for 48 h. Likewise, these compounds showed significantly lower toxicity against normal cells CHO-K1. The results suggest that native peptide fragments from Ps2Aa1 may be optimized as a novel potential cancer –therapeutic agents.

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Cancer cells optimize elasticity for efficient migration

Royal Society Open Science ◽

10.1098/rsos.200747 ◽

2020 ◽

Vol 7 (10) ◽

pp. 200747

Author(s):

Ahmad Sohrabi Kashani ◽

Muthukumaran Packirisamy

Keyword(s):

Mechanical Properties ◽

Cell Migration ◽

Cancer Cells ◽

Cancer Progression ◽

Computational Study ◽

Approximate Model ◽

Physical Parameters ◽

Force Transmission ◽

Two Parameters ◽

Contractile Forces

Cancer progression is associated with alternations in the cytoskeletal architecture of cells and, consequently, their mechanical properties such as stiffness. Changing the mechanics of cells enables cancer cells to migrate and invade to distant organ sites. This process, metastasis, is the main reason for cancer-related mortality. Cell migration is an essential step towards increasing the invasive potential of cells. Although many studies have shown that the migratory speed and the invasion of cells can be inversely correlated to the stiffness of cells, some other investigations indicate opposing results. In the current work, based on the strain energy stored in cells due to the contractile forces, we defined an energy-dependent term, migratory index, to approximate how changes in the mechanical properties of cells influence cell migration required for cancer progression. Cell migration involves both cell deformation and force transmission within cells. The effects of these two parameters can be represented equally by the migratory index. Our mechanical modelling and computational study show that cells depending on their shape, size and other physical parameters have a maximum migratory index taking place at a specific range of cell bulk elasticity, indicating the most favourable conditions for invasive mobility. This approximate model could be used to explain why the stiffness of cells varies during cancer progression. We believe that the stiffness of cancer or malignant cells depending on the stiffness of their normal or non-malignant counterparts is either decreased or increased to reach the critical condition in which the mobility potential of cells is approximated to be maximum.

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Molecular insights into the Patched1 drug efflux inhibitory activity of panicein A hydroquinone: a computational study

Physical Chemistry Chemical Physics ◽

10.1039/d0cp05719c ◽

2021 ◽

Author(s):

Sandra Kovachka ◽

Giuliano Malloci ◽

Attilio Vittorio Vargiu ◽

Stéphane Azoulay ◽

Isabelle Mus-Veteau ◽

...

Keyword(s):

Multidrug Resistance ◽

Cancer Cells ◽

Inhibitory Activity ◽

Chemical Structure ◽

Computational Study ◽

Drug Efflux ◽

Tumor Treatment

Human Hedgehog receptor Patched1 is able to efflux chemotherapeutics of different chemical structure out of cancer cells thus contributing to multidrug resistance phenomena in tumor treatment.

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