Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies.

1 year 5 months ago
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Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies.

Int J Mol Sci. 2018 Feb 14;19(2):

Authors: Grasso G, Rebella M, Muscat S, Morbiducci U, Tuszynski J, Danani A, Deriu MA

Abstract
Alzheimer's disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid β (Aβ) oligomers in the brain of patients. Two principal variants of Aβ exist in humans: Aβ1-40 and Aβ1-42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of Aβ1-40 peptides can only assume U-shaped conformations while Aβ1-42 can also arrange as S-shaped three-stranded chains, as recently discovered. As alterations in protein conformational arrangement correlate with cell toxicity and speed of disease progression, it is important to characterize, at molecular level, the conformational dynamics of amyloid fibrils. In this work, Replica Exchange Molecular Dynamics simulations were carried out to compare the conformational dynamics of U-shaped and S-shaped Aβ17-42 small fibrils. Our computational results provide support for the stability of the recently proposed S-shaped model due to the maximized interactions involving the C-terminal residues. On the other hand, the U-shaped motif is characterized by significant distortions resulting in a more disordered assembly. Outcomes of our work suggest that the molecular architecture of the protein aggregates might play a pivotal role in formation and conformational stability of the resulting fibrils.

PMID: 29443891 [PubMed - indexed for MEDLINE]

Destabilizing the AXH Tetramer by Mutations: Mechanisms and Potential Antiaggregation Strategies.

1 year 5 months ago
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Destabilizing the AXH Tetramer by Mutations: Mechanisms and Potential Antiaggregation Strategies.

Biophys J. 2018 01 23;114(2):323-330

Authors: Grasso G, Morbiducci U, Massai D, Tuszynski JA, Danani A, Deriu MA

Abstract
The AXH domain of protein Ataxin 1 is thought to play a key role in the misfolding and aggregation pathway responsible for Spinocerebellar ataxia 1. For this reason, a molecular level understanding of AXH oligomerization pathway is crucial to elucidate the aggregation mechanism, which is thought to trigger the disease. This study employs classical and enhanced molecular dynamics to identify the structural and energetic basis of AXH tetramer stability. Results of this work elucidate molecular mechanisms behind the destabilizing effect of protein mutations, which consequently affect the AXH tetramer assembly. Moreover, results of the study draw attention for the first time, to our knowledge, to the R638 protein residue, which is shown to play a key role in AXH tetramer stability. Therefore, R638 might be also implicated in the AXH oligomerization pathway and stands out as a target for future experimental studies focused on self-association mechanisms and fibril formation of full-length ATX1.

PMID: 29401430 [PubMed - indexed for MEDLINE]

Optomechanical proposal for monitoring microtubule mechanical vibrations.

1 year 5 months ago
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Optomechanical proposal for monitoring microtubule mechanical vibrations.

Phys Rev E. 2017 Jul;96(1-1):012404

Authors: Barzanjeh S, Salari V, Tuszynski JA, Cifra M, Simon C

Abstract
Microtubules provide the mechanical force required for chromosome separation during mitosis. However, little is known about the dynamic (high-frequency) mechanical properties of microtubules. Here, we theoretically propose to control the vibrations of a doubly clamped microtubule by tip electrodes and to detect its motion via the optomechanical coupling between the vibrational modes of the microtubule and an optical cavity. In the presence of a red-detuned strong pump laser, this coupling leads to optomechanical-induced transparency of an optical probe field, which can be detected with state-of-the art technology. The center frequency and line width of the transparency peak give the resonance frequency and damping rate of the microtubule, respectively, while the height of the peak reveals information about the microtubule-cavity field coupling. Our method opens the new possibilities to gain information about the physical properties of microtubules, which will enhance our capability to design physical cancer treatment protocols as alternatives to chemotherapeutic drugs.

PMID: 29347215 [PubMed - indexed for MEDLINE]

Electromagnetic fields and optomechanics in cancer diagnostics and treatment.

1 year 6 months ago
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Electromagnetic fields and optomechanics in cancer diagnostics and treatment.

Front Biosci (Landmark Ed). 2018 03 01;23:1391-1406

Authors: Salari V, Barzanjeh S, Cifra M, Simon C, Scholkmann F, Alirezaei Z, Tuszynski JA

Abstract
In this paper, we discuss biological effects of electromagnetic (EM) fields in the context of cancer biology. In particular, we review the nanomechanical properties of microtubules (MTs), the latter being one of the most successful targets for cancer therapy. We propose an investigation on the coupling of electromagnetic radiation to mechanical vibrations of MTs as an important basis for biological and medical applications. In our opinion, optomechanical methods can accurately monitor and control the mechanical properties of isolated MTs in a liquid environment. Consequently, studying nanomechanical properties of MTs may give useful information for future applications to diagnostic and therapeutic technologies involving non-invasive externally applied physical fields. For example, electromagnetic fields or high intensity ultrasound can be used therapeutically avoiding harmful side effects of chemotherapeutic agents or classical radiation therapy.

PMID: 29293441 [PubMed - indexed for MEDLINE]

Are there optical communication channels in the brain?

1 year 6 months ago
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Are there optical communication channels in the brain?

Front Biosci (Landmark Ed). 2018 03 01;23:1407-1421

Authors: Zarkeshian P, Kumar S, Tuszynski J, Barclay P, Simon C

Abstract
Despite great progress in neuroscience, there are still fundamental unanswered questions about the brain, including the origin of subjective experience and consciousness. Some answers might rely on new physical mechanisms. Given that biophotons have been discovered in the brain, it is interesting to explore if neurons use photonic communication in addition to the well-studied electro-chemical signals. Such photonic communication in the brain would require waveguides. Here we review recent work (S. Kumar, K. Boone, J. Tuszynski, P. Barclay, and C. Simon, Scientific Reports 6, 36508 (2016)) suggesting that myelinated axons could serve as photonic waveguides. The light transmission in the myelinated axon was modeled, taking into account its realistic imperfections, and experiments were proposed both in vivo and in vitro to test this hypothesis. Potential implications for quantum biology are discussed.

PMID: 29293442 [PubMed - indexed for MEDLINE]

Self-Assembled Ligands Targeting TLR7: A Molecular Level Investigation.

1 year 7 months ago
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Self-Assembled Ligands Targeting TLR7: A Molecular Level Investigation.

Langmuir. 2017 12 19;33(50):14460-14471

Authors: Deriu MA, Cangiotti M, Grasso G, Licandro G, Lavasanifar A, Tuszynski JA, Ottaviani MF, Danani A

Abstract
Toll-like receptors (TLRs) are pattern recognition transmembrane proteins that play an important role in innate immunity. In particular, TLR7 plays a role in detecting nucleic acids derived from viruses and bacteria. The huge number of pathologies in which TLR7 is involved has led to an increasing interest in developing new compounds targeting this protein. Several conjugation strategies were proposed for TLR7 agonists to increase the potency while maintaining a low toxicity. In this work, we focus the attention on two promising classes of TLR7 compounds derived from the same pharmacophore conjugated with phospholipid and polyethylene glycol (PEG). A multidisciplinary investigation has been carried out by molecular dynamics (MD), dynamic light scattering (DLS), electron paramagnetic resonance (EPR), and cytotoxicity assessment. DLS and MD indicated how only the phospholipid conjugation provides the compound abilities to self-assemble in an orderly fashion with a maximal pharmacophore exposition to the solvent. Further EPR and cytotoxicity experiments highlighted that phospholipid compounds organize in stable aggregates and well interact with TLR7, whereas PEG conjugation was characterized by poorly stable aggregates at the cells surface. The methodological framework proposed in this study may be used to investigate, at a molecular level, the interactions generally occurring between aggregated ligands, to be used as drugs, and protein receptors.

PMID: 29200306 [PubMed - indexed for MEDLINE]

A dialogue on the issue of the "quantum brain" between consciousness and unconsciousness.

1 year 8 months ago
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A dialogue on the issue of the "quantum brain" between consciousness and unconsciousness.

J Integr Neurosci. 2017;16(s1):S13-S18

Authors: Cocchi M, Gabrielli F, Tonello L, Tuszynski J

Abstract
In this paper, we present some diverse points of view on the issue of the quantum brain.The paper is structured in the form of opening statements by each of the co-authors followed by comments and critique presented by the other co-authors. The main focus of the discussion is on the interplay between the state of being alive and consciousness, both of which possess characteristics of quantum physical states.

PMID: 29125495 [PubMed - indexed for MEDLINE]

Gibbs free energy as a measure of complexity correlates with time within C. elegans embryonic development.

1 year 9 months ago
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Gibbs free energy as a measure of complexity correlates with time within C. elegans embryonic development.

J Biol Phys. 2017 Dec;43(4):551-563

Authors: McGuire SH, Rietman EA, Siegelmann H, Tuszynski JA

Abstract
We investigate free energy behavior in the nematode Caenorhabditis elegans during embryonic development. Our approach utilizes publicly available gene expression data, which gives us a picture of developmental changes in protein concentration and, resultantly, chemical potential and free energy. Our results indicate a clear global relationship between Gibbs free energy and time spent in development and provide thermodynamic indicators of the large-scale biological events of cell division and differentiation.

PMID: 28929407 [PubMed - indexed for MEDLINE]

Explaining the Microtubule Energy Balance: Contributions Due to Dipole Moments, Charges, van der Waals and Solvation Energy.

1 year 9 months ago
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Explaining the Microtubule Energy Balance: Contributions Due to Dipole Moments, Charges, van der Waals and Solvation Energy.

Int J Mol Sci. 2017 Sep 22;18(10):

Authors: Ayoub AT, Staelens M, Prunotto A, Deriu MA, Danani A, Klobukowski M, Tuszynski JA

Abstract
Microtubules are the main components of mitotic spindles, and are the pillars of the cellular cytoskeleton. They perform most of their cellular functions by virtue of their unique dynamic instability processes which alternate between polymerization and depolymerization phases. This in turn is driven by a precise balance between attraction and repulsion forces between the constituents of microtubules (MTs)-tubulin dimers. Therefore, it is critically important to know what contributions result in a balance of the interaction energy among tubulin dimers that make up microtubules and what interactions may tip this balance toward or away from a stable polymerized state of tubulin. In this paper, we calculate the dipole-dipole interaction energy between tubulin dimers in a microtubule as part of the various contributions to the energy balance. We also compare the remaining contributions to the interaction energies between tubulin dimers and establish a balance between stabilizing and destabilizing components, including the van der Waals, electrostatic, and solvent-accessible surface area energies. The energy balance shows that the GTP-capped tip of the seam at the plus end of microtubules is stabilized only by - 9 kcal/mol, which can be completely reversed by the hydrolysis of a single GTP molecule, which releases + 14 kcal/mol and destabilizes the seam by an excess of + 5 kcal/mol. This triggers the breakdown of microtubules and initiates a disassembly phase which is aptly called a catastrophe.

PMID: 28937650 [PubMed - indexed for MEDLINE]

The gastrointestinal-brain axis in humans as an evolutionary advance of the root-leaf axis in plants: A hypothesis linking quantum effects of light on serotonin and auxin.

1 year 9 months ago
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The gastrointestinal-brain axis in humans as an evolutionary advance of the root-leaf axis in plants: A hypothesis linking quantum effects of light on serotonin and auxin.

J Integr Neurosci. 2018;17(2):227-237

Authors: Tonello L, Gashi B, Scuotto A, Cappello G, Cocchi M, Gabrielli F, Tuszynski JA

Abstract
Living organisms tend to find viable strategies under ambient conditions that optimize their search for, and utilization of, life-sustaining resources. For plants, a leading role in this process is performed by auxin, a plant hormone that drives morphological development, dynamics, and movement to optimize the absorption of light (through branches and leaves) and chemical "food" (through roots). Similarly to auxin in plants, serotonin seems to play an important role in higher animals, especially humans. Here, it is proposed that morphological and functional similarities between (i) plant leaves and the animal/human brain and (ii) plant roots and the animal/human gastro-intestinal tract have general features in common. Plants interact with light and use it for biological energy, whereas, neurons in the central nervous system seem to interact with bio-photons and use them for proper brain function. Further, as auxin drives roots "arborescence" within the soil, similarly serotonin seems to facilitate enteric nervous system connectivity within the human gastro-intestinal tract. This auxin/serotonin parallel suggests the root-branches axis in plants may be an evolutionary precursor to the gastro-intestinal-brain axis in humans. Finally, we hypothesize that light might be an important factor, both in gastro-intestinal dynamics and brain function. Such a comparison may indicate a key role for the interaction of light and serotonin in neuronal physiology (possibly in both the central nervous system and the enteric nervous system), and according to recent work, mind and consciousness.

PMID: 28922165 [PubMed - indexed for MEDLINE]

Inhibitory Activity of Iron Chelators ATA and DFO on MCF-7 Breast Cancer Cells and Phosphatases PTP1B and SHP2.

1 year 10 months ago
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Inhibitory Activity of Iron Chelators ATA and DFO on MCF-7 Breast Cancer Cells and Phosphatases PTP1B and SHP2.

Anticancer Res. 2017 09;37(9):4799-4806

Authors: Kuban-Jankowska A, Sahu KK, Gorska-Ponikowska M, Tuszynski JA, Wozniak M

Abstract
BACKGROUND: Rapidly-dividing cancer cells have higher requirement for iron compared to non-transformed cells, making iron chelating a potential anticancer strategy. In the present study we compared the anticancer activity of uncommon iron chelator aurintricarboxylic acid (ATA) with the known deferoxamine (DFO).
MATERIALS AND METHODS: We investigated the impact of ATA and DFO on the viability and proliferation of MCF-7 cancer cells. Moreover we performed enzymatic activity assays and computational analysis of the ATA and DFO effects on pro-oncogenic phosphatases PTP1B and SHP2.
RESULTS: ATA and DFO decrease the viability and proliferation of breast cancer cells, but only ATA considerably reduces the activity of PTP1B and SHP2 phosphatases. Our studies indicated that ATA strongly inactivates and binds in the PTP1B and SHP2 active site, interacting with arginine residue essential for enzyme activity.
CONCLUSION: We confirmed that iron chelating can be considered as a potential strategy for the adjunctive treatment of breast cancer.

PMID: 28870898 [PubMed - indexed for MEDLINE]

Activation of hydrogen peroxide to peroxytetradecanoic acid is responsible for potent inhibition of protein tyrosine phosphatase CD45.

1 year 10 months ago
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Activation of hydrogen peroxide to peroxytetradecanoic acid is responsible for potent inhibition of protein tyrosine phosphatase CD45.

PLoS One. 2012;7(12):e52495

Authors: Kuban-Jankowska A, Tuszynski JA, Winter P, Gorska M, Knap N, Wozniak M

Abstract
Hydrogen peroxide induces oxidation and consequently inactivation of many protein tyrosine phosphatases. It was found that hydrogen peroxide, in the presence of carboxylic acids, was efficiently activated to form even more potent oxidant - peroxy acid. We have found that peroxytetradecanoic acid decreases the enzymatic activity of CD45 phosphatase significantly more than hydrogen peroxide. Our molecular docking computational analysis suggests that peroxytetradecanoic acid has a higher binding affinity to the catalytic center of CD45 than hydrogen peroxide.

PMID: 23300686 [PubMed - indexed for MEDLINE]

Experimental and computational study of the interaction of novel colchicinoids with a recombinant human αI/βI-tubulin heterodimer.

1 year 10 months ago
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Experimental and computational study of the interaction of novel colchicinoids with a recombinant human αI/βI-tubulin heterodimer.

Chem Biol Drug Des. 2013 Jul;82(1):60-70

Authors: Mane JY, Semenchenko V, Perez-Pineiro R, Winter P, Wishart D, Tuszynski JA

Abstract
The binding free energies on human tubulin of selected colchicine and thiocolchicine compounds were determined. Two methods were used for the determination of binding free energies: one is based on theoretical prediction simulating the dissociation of the compound from tubulin using a series of molecular dynamics simulations, and the other method involves a series of experiments that measured the affinity of the compound on a synthetically expressed and purified tubulin protein using a spectrofluorometric technique.

PMID: 23480279 [PubMed - indexed for MEDLINE]

Stochastic and Deterministic Models of Cellular p53 Regulation.

1 year 10 months ago
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Stochastic and Deterministic Models of Cellular p53 Regulation.

Front Oncol. 2013;3:64

Authors: Leenders GB, Tuszynski JA

Abstract
The protein p53 is a key regulator of cellular response to a wide variety of stressors. In cancer cells inhibitory regulators of p53 such as MDM2 and MDMX proteins are often overexpressed. We apply in silico techniques to better understand the role and interactions of these proteins in a cell cycle process. Furthermore we investigate the role of stochasticity in determining system behavior. We have found that stochasticity is able to affect system behavior profoundly. We also derive a general result for the way in which initially synchronized oscillating stochastic systems will fall out of synchronization with each other.

PMID: 23565502 [PubMed]

Small molecule inhibitors of ERCC1-XPF protein-protein interaction synergize alkylating agents in cancer cells.

1 year 10 months ago
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Small molecule inhibitors of ERCC1-XPF protein-protein interaction synergize alkylating agents in cancer cells.

Mol Pharmacol. 2013 Jul;84(1):12-24

Authors: Jordheim LP, Barakat KH, Heinrich-Balard L, Matera EL, Cros-Perrial E, Bouledrak K, El Sabeh R, Perez-Pineiro R, Wishart DS, Cohen R, Tuszynski J, Dumontet C

Abstract
The benefit of cancer chemotherapy based on alkylating agents is limited because of the action of DNA repair enzymes, which mitigate the damage induced by these agents. The interaction between the proteins ERCC1 and XPF involves two major components of the nucleotide excision repair pathway. Here, novel inhibitors of this interaction were identified by virtual screening based on available structures with use of the National Cancer Institute diversity set and a panel of DrugBank small molecules. Subsequently, experimental validation of the in silico screening was undertaken. Top hits were evaluated on A549 and HCT116 cancer cells. In particular, the compound labeled NSC 130813 [4-[(6-chloro-2-methoxy-9-acridinyl)amino]-2-[(4-methyl-1-piperazinyl)methyl]] was shown to act synergistically with cisplatin and mitomycin C; to increase UVC-mediated cytotoxicity; to modify DNA repair as indicated by the staining of phosphorylated H2AX; and to disrupt interaction between ERCC1 and XPF in cells. In addition, using the Biacore technique, we showed that this compound interacts with the domain of XPF responsible for interaction with ERCC1. This study shows that small molecules targeting the protein-protein interaction of ERCC1 and XPF can be developed to enhance the effects of alkylating agents on cancer cells.

PMID: 23580445 [PubMed - indexed for MEDLINE]

Determination of the optimal tubulin isotype target as a method for the development of individualized cancer chemotherapy.

1 year 10 months ago
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Determination of the optimal tubulin isotype target as a method for the development of individualized cancer chemotherapy.

Theor Biol Med Model. 2013 May 01;10:29

Authors: Ravanbakhsh S, Gajewski M, Greiner R, Tuszynski JA

Abstract
BACKGROUND: As microtubules are essential for cell growth and division, its constituent protein β-tubulin has been a popular target for various treatments, including cancer chemotherapy. There are several isotypes of human β-tubulin and each type of cell expresses its characteristic distribution of these isotypes. Moreover, each tubulin-binding drug has its own distribution of binding affinities over the various isotypes, which further complicates identifying the optimal drug selection. An ideal drug would preferentially bind only the tubulin isotypes expressed abundantly by the cancer cells, but not those in the healthy cells. Unfortunately, as the distributions of the tubulin isotypes in cancer cells overlap with those of healthy cells, this ideal scenario is clearly not possible. We can, however, seek a drug that interferes significantly with the isotype distribution of the cancer cell, but has only minor interactions with those of the healthy cells.
METHODS: We describe a quantitative methodology for identifying this optimal tubulin isotype profile for an ideal cancer drug, given the isotype distribution of a specific cancer type, as well as the isotype distributions in various healthy tissues, and the physiological importance of each such tissue.
RESULTS: We report the optimal isotype profiles for different types of cancer with various routes of delivery.
CONCLUSIONS: Our algorithm, which defines the best profile for each type of cancer (given the drug delivery route and some specified patient characteristics), will help to personalize the design of pharmaceuticals for individual patients. This paper is an attempt to explicitly consider the effects of the tubulin isotype distributions in both cancer and normal cell types, for rational chemotherapy design aimed at optimizing the drug's efficacy with minimal side effects.

PMID: 23634782 [PubMed - indexed for MEDLINE]

An integrated multidisciplinary model describing initiation of cancer and the Warburg hypothesis.

1 year 10 months ago
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An integrated multidisciplinary model describing initiation of cancer and the Warburg hypothesis.

Theor Biol Med Model. 2013 Jun 10;10:39

Authors: Rietman EA, Friesen DE, Hahnfeldt P, Gatenby R, Hlatky L, Tuszynski JA

Abstract
BACKGROUND: In this paper we propose a chemical physics mechanism for the initiation of the glycolytic switch commonly known as the Warburg hypothesis, whereby glycolytic activity terminating in lactate continues even in well-oxygenated cells. We show that this may result in cancer via mitotic failure, recasting the current conception of the Warburg effect as a metabolic dysregulation consequent to cancer, to a biophysical defect that may contribute to cancer initiation.
MODEL: Our model is based on analogs of thermodynamic concepts that tie non-equilibrium fluid dynamics ultimately to metabolic imbalance, disrupted microtubule dynamics, and finally, genomic instability, from which cancers can arise. Specifically, we discuss how an analog of non-equilibrium Rayleigh-Benard convection can result in glycolytic oscillations and cause a cell to become locked into a higher-entropy state characteristic of cancer.
CONCLUSIONS: A quantitative model is presented that attributes the well-known Warburg effect to a biophysical mechanism driven by a convective disturbance in the cell. Contrary to current understanding, this effect may precipitate cancer development, rather than follow from it, providing new insights into carcinogenesis, cancer treatment, and prevention.

PMID: 23758735 [PubMed - indexed for MEDLINE]

Biophysical insights into cancer transformation and treatment.

1 year 10 months ago
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Biophysical insights into cancer transformation and treatment.

ScientificWorldJournal. 2013;2013:195028

Authors: Pokorný J, Foletti A, Kobilková J, Jandová A, Vrba J, Vrba J, Nedbalová M, Čoček A, Danani A, Tuszyński JA

Abstract
Biological systems are hierarchically self-organized complex structures characterized by nonlinear interactions. Biochemical energy is transformed into work of physical forces required for various biological functions. We postulate that energy transduction depends on endogenous electrodynamic fields generated by microtubules. Microtubules and mitochondria colocalize in cells with microtubules providing tracks for mitochondrial movement. Besides energy transformation, mitochondria form a spatially distributed proton charge layer and a resultant strong static electric field, which causes water ordering in the surrounding cytosol. These effects create conditions for generation of coherent electrodynamic field. The metabolic energy transduction pathways are strongly affected in cancers. Mitochondrial dysfunction in cancer cells (Warburg effect) or in fibroblasts associated with cancer cells (reverse Warburg effect) results in decreased or increased power of the generated electromagnetic field, respectively, and shifted and rebuilt frequency spectra. Disturbed electrodynamic interaction forces between cancer and healthy cells may favor local invasion and metastasis. A therapeutic strategy of targeting dysfunctional mitochondria for restoration of their physiological functions makes it possible to switch on the natural apoptotic pathway blocked in cancer transformed cells. Experience with dichloroacetate in cancer treatment and reestablishment of the healthy state may help in the development of novel effective drugs aimed at the mitochondrial function.

PMID: 23844381 [PubMed - indexed for MEDLINE]

Similarity-based virtual screening for microtubule stabilizers reveals novel antimitotic scaffold.

1 year 10 months ago
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Similarity-based virtual screening for microtubule stabilizers reveals novel antimitotic scaffold.

J Mol Graph Model. 2013 Jul;44:188-96

Authors: Ayoub AT, Klobukowski M, Tuszynski J

Abstract
Microtubules are among the most studied and best characterized cancer targets identified to date. Many microtubule stabilizers have been introduced so far that work by disrupting the dynamic instability of microtubules causing mitotic block and apoptosis. However, most of these molecules, especially taxol and epothilone, suffer absorption, toxicity and/or resistance problems. Here we employ a novel similarity-based virtual screening approach in the hope of finding other microtubule stabilizers that perform better and have lower toxicity and resistance. Epothilones, discodermolide, eleutherobin and sarcodictyin A have been found to compete with taxanes for the β-tubulin binding site, which suggests common chemical features qualifying for that. Our approach was based on similarity screening against all these compounds and other microtubule stabilizers, followed by virtual screening against the taxol binding site. Some novel hits were found, together with a novel highly rigid molecular scaffold. After visual manipulations, redocking and rescoring of this novel scaffold, its affinity dramatically increased in a promising trend, which qualifies for biological testing.

PMID: 23871820 [PubMed - indexed for MEDLINE]