GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets
Synthesis, antiproliferative activity, and molecular docking studies of 4-chlorothiocolchicine analogues
Probing the Basis of α-Synuclein Aggregation by Comparing Simulations to Single-Molecule Experiments
Tubulin Polarizability in Aqueous Suspensions
Magnetic Monopole Search with the Full MoEDAL Trapping Detector in 13 TeV pp Collisions Interpreted in Photon-Fusion and Drell-Yan Production
Targeting DNA Repair in Tumor Cells via Inhibition of ERCC1-XPF
Tubulin response to intense nanosecond-scale electric field in molecular dynamics simulation
How signals of calcium ions initiate the beats of cilia and flagella
Molecular orbitals of delocalized electron clouds in neuronal domains
The Role of Structural Polymorphism in Driving the Mechanical Performance of the Alzheimer's Beta Amyloid Fibrils
Theorizing how the brain encodes consciousness based on negentropic entanglement
An Overview of Molecular Modeling for Drug Discovery with Specific Illustrative Examples of Applications.
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]
The molecular mechanism of action of methylene quinuclidinone and its effects on the structure of p53 mutants.
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]
The Bioelectric Circuitry of the Cell
Simulating the Effect of 200 kHz AC Electric Fields on Tumour Cell Structures to Uncover the Mechanism of a Cancer Therapy
EDEn-Electroceutical Design Environment: Ion Channel Tissue Expression Database with Small Molecule Modulators.
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]
Synthesis of small peptide compounds, molecular docking, and inhibitory activity evaluation against phosphatases PTP1B and SHP2.
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]
Synthesis and Biological Evaluation of Novel Triple-Modified Colchicine Derivatives as Potent Tubulin-Targeting Anticancer Agents.
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]
Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives.
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]