Colchicine is the major alkaloid isolated from the plant Colchicum autumnale, which shows strong therapeutic effects towards different types of cancer. However, due to the toxicity of colchicine towards normal cells its application is limited. To address this issue we synthesized a series of seven triple-modified 4-bromothiocolchicine analogues with amide moieties. These novel derivatives were active in the nanomolar range against several different cancer cell lines and primary acute...

Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor, portending a median 13-month survival even following gross total resection with adjuvant chemotherapy and radiotherapy. This prognosis necessitates improved therapies for the disease. A target of interest for novel chemotherapies is the Warburg Effect, which describes the tumor's shift away from oxidative phosphorylation towards glycolysis. Here, we elucidate GLUT1 (Glucose transporter 1) and one of its associated...

Colchicine is a therapeutic agent currently used in therapies of many diseases. It also shows antimitotic effects, and its high cytotoxic activity against different cancer cell lines has been demonstrated many times. To overcome the limitations of colchicine use in anticancer therapy, we synthesized a series of novel triple-modified 4-chloro-7-carbamatethiocolchicines. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX, and...

Intrinsically disordered proteins often play an important role in protein aggregation. However, it is challenging to determine the structures and interactions that drive the early stages of aggregation because they are transient and obscured in a heterogeneous mixture of disordered states. Even computational methods are limited because the lack of ordered structure makes it difficult to ensure that the relevant conformations are sampled. We address these challenges by integrating atomistic...

We report accurate optical measurements of tubulin polarizability in aqueous suspensions. We determined the dependence of polarizability on tubulin concentration and on the suspension's pH, providing benchmark numbers for quantifying the optical response of this protein in various artificial and cellular environments. We compare our measurement data with a few estimates found in the previous literature and also with our simplified model estimations.

MoEDAL is designed to identify new physics in the form of stable or pseudostable highly ionizing particles produced in high-energy Large Hadron Collider (LHC) collisions. Here we update our previous search for magnetic monopoles in Run 2 using the full trapping detector with almost four times more material and almost twice more integrated luminosity. For the first time at the LHC, the data were interpreted in terms of photon-fusion monopole direct production in addition to the Drell-Yan-like...

The ERCC1-XPF heterodimer is a 5'-3' structure-specific endonuclease, which plays an essential role in several DNA repair pathways in mammalian cells. ERCC1-XPF is primarily involved in the repair of chemically induced helix-distorting and bulky DNA lesions, such as cyclobutane pyrimidine dimers (CPDs), and DNA interstrand cross-links. Inhibition of ERCC1-XPF has been shown to potentiate cytotoxicity of platinum-based drugs and cyclophosphamide in cancer cells. In this study, the previously...

Intense pulsed electric fields are known to act at the cell membrane level and are already being exploited in biomedical and biotechnological applications. However, it is not clear if electric pulses within biomedically-attainable parameters could directly influence intra-cellular components such as cytoskeletal proteins. If so, a molecular mechanism of action could be uncovered for therapeutic applications of such electric fields. To help clarify this question, we first identified that a...

Cilia and flagella are cell organelles serving basic roles in cellular motility. Ciliary movement is performed by a sweeping-like repeated bending motion, which gives rise to a self-propagating "ciliary beat". The hallmark structure in cilia is the axoneme, a stable architecture of microtubule doublets. The motion of axoneme is powered by the axonemal dynein motor family powered by ATP hydrolysis. It is still unclear how the organized beat of cilium and flagella emerges from the combined action...

We have further developed the two-brains hypothesis as a form of complementarity (or complementary relationship) of endogenously induced weak magnetic fields in the electromagnetic brain. The locally induced magnetic field between electron magnetic dipole moments of delocalized electron clouds in neuronal domains is complementary to the exogenous electromagnetic waves created by the oscillating molecular dipoles in the electro-ionic brain. In this paper, we mathematically model the operation of...

Alzheimer's Disease (AD) is related with the abnormal aggregation of amyloid β-peptides Aβ(1-40) and Aβ(1-42), the latter having a polymorphic character which gives rise to U- or S-shaped fibrils. Elucidating the role played by the nanoscale-material architecture on the amyloid fibril stability is a crucial breakthrough to better understand the pathological nature of amyloid structures and to support the rational design of bio-inspired materials. The computational study here presented highlights...

The physicality of subjectivity is explained through a theoretical conceptualization of guidance waves informing meaning in negentropically entangled non-electrolytic brain regions. Subjectivity manifests its influence at the microscopic scale of matter originating from de Broglie 'hidden' thermodynamics as action of guidance waves. The preconscious experienceability of subjectivity is associated with a nested hierarchy of microprocesses, which are actualized as a continuum of patterns of...

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An Overview of Molecular Modeling for Drug Discovery with Specific Illustrative Examples of Applications.

Molecules. 2019 Apr 30;24(9):

Authors: Aminpour M, Montemagno C, Tuszynski JA

Abstract
In this paper we review the current status of high-performance computing applications in the general area of drug discovery. We provide an introduction to the methodologies applied at atomic and molecular scales, followed by three specific examples of implementation of these tools. The first example describes in silico modeling of the adsorption of small molecules to organic and inorganic surfaces, which may be applied to drug delivery issues. The second example involves DNA translocation through nanopores with major significance to DNA sequencing efforts. The final example offers an overview of computer-aided drug design, with some illustrative examples of its usefulness.

PMID: 31052253 [PubMed - indexed for MEDLINE]

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The molecular mechanism of action of methylene quinuclidinone and its effects on the structure of p53 mutants.

Oncotarget. 2018 Dec 14;9(98):37137-37156

Authors: Omar SI, Tuszynski J

Abstract
One of the most important tumor suppressor proteins in eukaryotic cells is the transcription factor called p53. The importance of this protein in cells comes from the fact that it regulates a wide variety of cellular processes including the cell cycle, metabolism, DNA repair, senescence and apoptosis. In cancer cells, p53 is a major target as the most mutated protein, which has led to the search for potential activators of the mutant protein. Currently, the only mutated-p53 activator in clinical trials is a small molecule called APR-246. There is evidence that the active metabolite of APR-246 binds covalently to mutant p53 and restores its wild-type (wt) activity. In this work, we created atomistic in silico models of the wt, mutant and drugged mutant p53 proteins each in complex with DNA. Using molecular dynamics simulations we generated equilibrated models of the complexes. Detailed analysis revealed that the binding of the APR-246 active metabolite to the mutant proteins alters their interaction with DNA. In particular, the binding of the molecule at loop L1 of the protein allows the loop to anchor the protein to DNA similarly to wt p53. Several important p53-DNA interactions lost due to mutation were also restored in the drugged mutants. These findings, not only provide a possible mechanism of action of this drug, but also criteria to use in virtual screening campaigns for other p53 activators.

PMID: 30647850 [PubMed]

This chapter presents an overview of electric conduction in living cells when viewed as a composition of bioelectric circuits. We review the cell’s components that are known to exhibit electric conduction properties and represent them as parts of a complex circuitry. In particular, we discuss conductivity of the membrane, ion channels, actin filaments, DNA, and microtubules, each of which play important roles in the biological functioning of the cell. A new picture emerges where electrical...

Our goal is to uncover the mechanism underlying tumour-treating fields’ efficacy in killing cancer cells. Modelling the effects of these 200 kHz alternating current electric fields on tumour cell sub-structures has led us to focus on the microtubules (MTs), C-termini and the motor protein kinesin, which are integral to the critical functions of MT transport of proteins during the delicate orchestration of cell division (mitosis). Leading hypotheses of the TTFields’ mechanism that we are...

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EDEn-Electroceutical Design Environment: Ion Channel Tissue Expression Database with Small Molecule Modulators.

iScience. 2018 Dec 11;11:42-56

Authors: Churchill CDM, Winter P, Tuszynski JA, Levin M

Abstract
The emerging field of bioelectricity has revealed numerous new roles for ion channels beyond the nervous system, which can be exploited for applications in regenerative medicine. Developing such biomedical interventions for birth defects, cancer, traumatic injury, and bioengineering first requires knowledge of ion channel targets expressed in tissues of interest. This information can then be used to select combinations of small molecule inhibitors and/or activators that manipulate the bioelectric state. Here, we provide an overview of electroceutical design environment (EDEn), the first bioinformatic platform that facilitates the design of such therapeutic strategies. This database includes information on ion channels and ion pumps, linked to known chemical modulators and their properties. The database also provides information about the expression levels of the ion channels in over 100 tissue types. The graphical interface allows the user to readily identify chemical entities that can alter the electrical properties of target cells and tissues.

PMID: 30590250 [PubMed - as supplied by publisher]

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Synthesis of small peptide compounds, molecular docking, and inhibitory activity evaluation against phosphatases PTP1B and SHP2.

Drug Des Devel Ther. 2018;12:4139-4147

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

Abstract
Background: The protein tyrosine phosphatases PTP1B and SHP2 are promising drug targets in treatment design for breast cancer. Searching for specific inhibitors of their activity has recently become the challenge of many studies. Previous work has indicated that the promising PTP inhibitors may be small compounds that are able to bind and interact with amino residues from the binding site.
Purpose: The main goal of our study was to synthesize and analyze the effect of selected small peptide inhibitors on oncogenic PTP1B and SHP2 enzymatic activity and viability of MCF7 breast cancer cells. We also performed computational analysis of peptides binding with allosteric sites of PTP1B and SHP2 phosphatases.
Methods: We measured the inhibitory activity of compounds utilizing recombinant enzymes and MCF7 cell line. Computational analysis involved docking studies of binding conformation and interactions of inhibitors with allosteric sites of phosphatases.
Results: The results showed that the tested compounds decrease the enzymatic activity of phosphatases PTP1B and SHP2 with IC50 values in micromolar ranges. We observed higher inhibitory activity of dipeptides than tripeptides. Phe-Asp was the most effective against SHP2 enzymatic activity, with IC50=5.2±0.4 µM. Micromolar concentrations of tested dipeptides also decreased the viability of MCF7 breast cancer cells, with higher inhibitory activity observed for the Phe-Asp peptide. Moreover, the peptides tested were able to bind and interact with allosteric sites of PTP1B and SHP2 phosphatases.
Conclusion: Our research showed that small peptide compounds can be considered for the design of specific inhibitors of oncogenic protein tyrosine phosphatases.

PMID: 30584278 [PubMed - indexed for MEDLINE]

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Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents.

Cells. 2018 Nov 19;7(11):

Authors: Majcher U, Klejborowska G, Kaik M, Maj E, Wietrzyk J, Moshari M, Preto J, Tuszynski JA, Huczyński A

Abstract
Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple-modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of β-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin.

PMID: 30463236 [PubMed]

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Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives.

Cells. 2018 Nov 01;7(11):

Authors: Majcher U, Klejborowska G, Moshari M, Maj E, Wietrzyk J, Bartl F, Tuszynski JA, Huczyński A

Abstract
Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer agent with a known antimitotic effect on cells. However, the use of colchicine as well as many of its derivatives in long-term treatment is hampered by their high toxicity. To create more potent anticancer agents, three novel double-modified colchicine derivatives have been obtained by structural modifications in C-4 and C-10 positions. The binding affinities of these derivatives of colchicine with respect to eight different isotypes of human β-tubulin have been calculated using docking methods. In vitro cytotoxicity has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo and LoVo/DX). Computer simulations predicted the binding modes of these compounds and hence the key residues involved in the interactions between tubulin and the colchicine derivatives. Two of the obtained derivatives, 4-bromothiocolchicine and 4-iodothiocolchicine, were shown to be active against three of the investigated cancer cell lines (A549, MCF-7, LoVo) with potency at nanomolar concentrations and a higher relative affinity to tumor cells over normal cells.

PMID: 30388878 [PubMed]