Analysis of the binding mode of laulimalide to microtubules: Establishing a laulimalide-tubulin pharmacophore.

1 year 10 months ago
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Analysis of the binding mode of laulimalide to microtubules: Establishing a laulimalide-tubulin pharmacophore.

J Biomol Struct Dyn. 2016 Jul;34(7):1455-69

Authors: Churchill CD, Klobukowski M, Tuszynski JA

Abstract
Laulimalide (LA) is a microtubule-stabilizing agent, currently in preclinical studies. However, studying the binding of this species and successfully synthesizing potent analogues have been challenging. The LA binding site is located between tubulin protofilaments, and therefore LA is in contact with two adjacent [Formula: see text]-tubulin units. Here, an improved model of the binding mode of LA in microtubules is presented, using the newly available crystal structure pose and an extended tubulin heterodimer complex, as well as molecular dynamics simulations. With this model, a series of LA analogues developed by Mooberry and coworkers are also analyzed in order to establish important pharmacophores in LA binding and cytotoxicity. In the side chain, [Formula: see text]-[Formula: see text] interactions are important contributors to LA binding, as are water-mediated hydrogen bonds. An intramolecular hydrogen bond is correlated with high cytotoxicity, and is dependent on macrocycle conformation. Therefore, while the epoxide and olefin groups in the macrocycle do not engage in specific interactions with the protein, they are essential contributions to an active macrocycle conformation, and therefore potency. Calculations reveal that a balance in binding affinity is important for LA activity, where the more potent compounds have larger interactions with the adjacent tubulin unit than the less-active analogs. Several modifications are suggested for the rational design of LA analogues that should not disrupt the active macrocycle conformation.

PMID: 26230757 [PubMed - indexed for MEDLINE]

The use of compressive sensing and peak detection in the reconstruction of microtubules length time series in the process of dynamic instability.

1 year 10 months ago
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The use of compressive sensing and peak detection in the reconstruction of microtubules length time series in the process of dynamic instability.

Comput Biol Med. 2015 Oct 01;65:25-33

Authors: Mahrooghy M, Yarahmadian S, Menon V, Rezania V, Tuszynski JA

Abstract
Microtubules (MTs) are intra-cellular cylindrical protein filaments. They exhibit a unique phenomenon of stochastic growth and shrinkage, called dynamic instability. In this paper, we introduce a theoretical framework for applying Compressive Sensing (CS) to the sampled data of the microtubule length in the process of dynamic instability. To reduce data density and reconstruct the original signal with relatively low sampling rates, we have applied CS to experimental MT lament length time series modeled as a Dichotomous Markov Noise (DMN). The results show that using CS along with the wavelet transform significantly reduces the recovery errors comparing in the absence of wavelet transform, especially in the low and the medium sampling rates. In a sampling rate ranging from 0.2 to 0.5, the Root-Mean-Squared Error (RMSE) decreases by approximately 3 times and between 0.5 and 1, RMSE is small. We also apply a peak detection technique to the wavelet coefficients to detect and closely approximate the growth and shrinkage of MTs for computing the essential dynamic instability parameters, i.e., transition frequencies and specially growth and shrinkage rates. The results show that using compressed sensing along with the peak detection technique and wavelet transform in sampling rates reduces the recovery errors for the parameters.

PMID: 26275388 [PubMed - indexed for MEDLINE]

Redox process is crucial for inhibitory properties of aurintricarboxylic acid against activity of YopH: virulence factor of Yersinia pestis.

1 year 10 months ago
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Redox process is crucial for inhibitory properties of aurintricarboxylic acid against activity of YopH: virulence factor of Yersinia pestis.

Oncotarget. 2015 Jul 30;6(21):18364-73

Authors: Kuban-Jankowska A, Sahu KK, Niedzialkowski P, Gorska M, Tuszynski JA, Ossowski T, Wozniak M

Abstract
YopH is a bacterial protein tyrosine phosphatase, which is essential for the viability and pathogenic virulence of the plague-causing Yersinia sp. bacteria. Inactivation of YopH activity would lead to the loss of bacterial pathogenicity. We have studied the inhibitory properties of aurintricarboxylic acid (ATA) against YopH phosphatase and found that at nanomolar concentrations ATA reversibly decreases the activity of YopH. Computational docking studies indicated that in all binding poses ATA binds in the YopH active site. Molecular dynamics simulations showed that in the predicted binding pose, ATA binds to the essential Cys403 and Arg409 residues in the active site and has a stronger binding affinity than the natural substrate (pTyr). The cyclic voltammetry experiments suggest that ATA reacts remarkably strongly with molecular oxygen. Additionally, the electrochemical reduction of ATA in the presence of a negative potential from -2.0 to 2.5 V generates a current signal, which is observed for hydrogen peroxide. Here we showed that ATA indicates a unique mechanism of YopH inactivation due to a redox process. We proposed that the potent inhibitory properties of ATA are a result of its strong binding in the YopH active site and in situ generation of hydrogen peroxide near catalytic cysteine residue.

PMID: 26286963 [PubMed - indexed for MEDLINE]

Modeling the energetic cost of cancer as a result of altered energy metabolism: implications for cachexia.

1 year 10 months ago
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Modeling the energetic cost of cancer as a result of altered energy metabolism: implications for cachexia.

Theor Biol Med Model. 2015 Sep 15;12:17

Authors: Friesen DE, Baracos VE, Tuszynski JA

Abstract
BACKGROUND: Cachexia affects most patients with incurable cancer. We hypothesize that in metastatic cancer the mass of the tumor as well as its level of anaerobic energy metabolism play a critical role in describing its energetic cost, which results in elevated resting energy expenditure and glucose utilization, leading to cachexia. Prior models of cancer cachexia may have underestimated the specific energetic cost of cancer as they have not taken the range of tumor mass and anaerobic energy metabolism fully into account.
METHODS: We therefore modelled the energetic cost of cancer as a function of the percentage of energy the cancer produces anaerobically, based on resting energy expenditure, glucose turnover, glucose recycling, and oxygen consumption in cancer patients found in previous studies.
RESULTS: Data from two clinical studies where tumor burden was estimated and resting energy expenditure or oxygen consumption were measured lead to a broad range of estimates of tumor cost from 190 to 470 kcal/kg tumor/day. These values will vary based of the percentage of energy the cancer produces anaerobically (from 0 to 100%), which in and of itself can alter the cost over a 2 to 3-fold range. In addition to the tumor cost/kg and the degree of anaerobic metabolism, the impact on a given individual patient will depend on tumor burden, which can exceed 1 kg in advanced metastatic disease. Considering these dimensions of tumor cost we are able to produce a 2-dimensional map of potential values, with an overall range of 100-1400 kcal/day.
CONCLUSIONS: Quantifying the energetic cost of cancer may benefit an understanding of the tumor's causation of cachexia. Our estimates of the range of tumor cost include values that are higher than prior estimates and suggest that in metastatic disease the tumor cost could be expected to eclipse attempts to stabilize energy balance through nutrition support or by drug therapies. Tumor mass and the percentage of anaerobic metabolism in the tumor contribute to the cost of the tumor on the body and potentially lead directly to negative energy balance and increased muscle wasting.

PMID: 26370269 [PubMed - indexed for MEDLINE]

The physiological concentration of ferrous iron (II) alters the inhibitory effect of hydrogen peroxide on CD45, LAR and PTP1B phosphatases.

1 year 10 months ago
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The physiological concentration of ferrous iron (II) alters the inhibitory effect of hydrogen peroxide on CD45, LAR and PTP1B phosphatases.

Biometals. 2015 Dec;28(6):975-86

Authors: Kuban-Jankowska A, Gorska M, Jaremko L, Jaremko M, Tuszynski JA, Wozniak M

Abstract
Hydrogen peroxide is an important regulator of protein tyrosine phosphatase activity via reversible oxidation. However, the role of iron in this reaction has not been yet elucidated. Here we compare the influence of hydrogen peroxide and the ferrous iron (reagent for Fenton reaction) on the enzymatic activity of recombinant CD45, LAR, PTP1B phosphatases and cellular CD45 in Jurkat cells. The obtained results show that ferrous iron (II) is potent inhibitor of CD45, LAR and PTP1B, but the inhibitory effect is concentration dependent. We found that the higher concentrations of ferrous iron (II) increase the inactivation of CD45, LAR and PTP1B phosphatase caused by hydrogen peroxide, but the addition of the physiological concentration (500 nM) of ferrous iron (II) has even a slightly preventive effect on the phosphatase activity against hydrogen peroxide.

PMID: 26407665 [PubMed - indexed for MEDLINE]

Conformational fluctuations of the AXH monomer of Ataxin-1.

1 year 10 months ago
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Conformational fluctuations of the AXH monomer of Ataxin-1.

Proteins. 2016 Jan;84(1):52-9

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

Abstract
In this paper, we report the results of molecular dynamics simulations of AXH monomer of Ataxin-1. The AXH domain plays a crucial role in Ataxin-1 aggregation, which accompanies the initiation and progression of Spinocerebellar ataxia type 1. Our simulations involving both classical and replica exchange molecular dynamics, followed by principal component analysis of the trajectories obtained, reveal substantial conformational fluctuations of the protein structure, especially in the N-terminal region. We show that these fluctuations can be generated by thermal noise since the free energy barriers between conformations are small enough for thermally stimulated transitions. In agreement with the previous experimental findings, our results can be considered as a basis for a future design of ataxin aggregation inhibitors that will require several key conformations identified in the present study as molecular targets for ligand binding.

PMID: 26522012 [PubMed - indexed for MEDLINE]

Entropic analysis reveals a connection between the recurrence of cancer and chemotherapy.

1 year 10 months ago
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Entropic analysis reveals a connection between the recurrence of cancer and chemotherapy.

Saudi J Biol Sci. 2015 Nov;22(6):674-8

Authors: Tseng CY, Tuszynski J

Abstract
In this study, we proposed an entropic analysis to overcome limitations of conventional statistical methods to analyze clinical data for cancer patients who experienced relapse of tumors following chemotherapy. We have applied this entropic method to reveal potential mechanisms that lead to a relapse of Wilms' tumor in pediatric patients. Results indicate β-tubulin isotype III up-regulation is likely the primary cause of the relapse.

PMID: 26586992 [PubMed]

Isolation of soluble scFv antibody fragments specific for small biomarker molecule, L-Carnitine, using phage display.

1 year 10 months ago
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Isolation of soluble scFv antibody fragments specific for small biomarker molecule, L-Carnitine, using phage display.

J Immunol Methods. 2016 Jan;428:9-19

Authors: Abou El-Magd RM, Vozza NF, Tuszynski JA, Wishart DS

Abstract
Isolation of single chain antibody fragment (scFv) clones from naïve Tomlinson I+J phage display libraries that specifically bind a small biomarker molecule, L-Carnitine, was performed using iterative affinity selection procedures. L-Carnitine has been described as a conditionally essential nutrient for humans. Abnormally high concentrations of L-Carnitine in urine are related to many health disorders including diabetes mellitus type 2 and lung cancer. ELISA-based affinity characterization results indicate that selectants preferentially bind to L-Carnitine in the presence of key bioselecting component materials and closely related L-Carnitine derivatives. In addition, the affinity results were confirmed using biophysical fluorescence quenching for tyrosine residues in the V segment. Small-scale production of the soluble fragment yielded 1.3mg/L using immunopure-immobilized protein A affinity column. Circular Dichroism data revealed that the antibody fragment (Ab) represents a folded protein that mainly consists of β-sheets. These novel antibody fragments may find utility as molecular affinity interface receptors in various electrochemical biosensor platforms to provide specific L-Carnitine binding capability with potential applications in metabolomic devices for companion diagnostics and personalized medicine applications. It may also be used in any other biomedical application where detection of the L-Carnitine level is important.

PMID: 26608419 [PubMed - indexed for MEDLINE]

Effect of CH-35, a novel anti-tumor colchicine analogue, on breast cancer cells overexpressing the βIII isotype of tubulin.

1 year 10 months ago
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Effect of CH-35, a novel anti-tumor colchicine analogue, on breast cancer cells overexpressing the βIII isotype of tubulin.

Invest New Drugs. 2016 Feb;34(1):129-37

Authors: Yeh LC, Banerjee A, Prasad V, Tuszynski JA, Weis AL, Bakos T, Yeh IT, Ludueña RF, Lee JC

Abstract
The subunit protein of microtubules is tubulin, which has been the target for some of the most successful and widely used anti-tumor drugs. Most of the drugs that target tubulin bind to the β subunit. There are many isotypes of β-tubulin and their distributions differ among different tissues. The βIII isotype is over-expressed in many tumors, particularly those that are aggressive, metastatic, and drug resistant. We have previously reported the design and synthesis of a series of compounds to fit the colchicine site on βIII but not on the other isotypes. In the current study, we tested the toxicity and the anti-tumor activity of one of these compounds, CH-35, on the human breast tumor MDA-MB-231 over-expressing βIII in a xenogeneic mouse model. We found that CH-35 was as toxic as Taxol® in vivo. Although the βIII-over-expressing cells developed into very fast-growing tumors, CH-35 was more effective against this tumor than was Taxol. Our results suggest that CH-35 is a promising candidate for future drug development.

PMID: 26686345 [PubMed - indexed for MEDLINE]

Phase transitions and structure analysis in wild-type, A30P, E46K, and A53T mutants of α-synuclein.

1 year 10 months ago
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Phase transitions and structure analysis in wild-type, A30P, E46K, and A53T mutants of α-synuclein.

Eur Biophys J. 2016 May;45(4):355-64

Authors: Healey MA, Woodside MT, Tuszynski JA

Abstract
α-Synuclein has been implicated in the development of neural plaques in Parkinson's Disease and Lewy-Body Dementia. This paper reports on the structural phase change behavior exhibited over a relevant range of temperatures in canonical protein Monte Carlo simulations for wild-type α-synuclein and three of its familial variants. We performed and analyzed these simulations to determine residue occupancy variations above and below this phase transition. From this analysis, we found regions above the phase transition temperature that consistently exhibited increased propensity for formation of long-chain beta-sheets, suggesting a possible role in α-synuclein aggregation.

PMID: 26695014 [PubMed - indexed for MEDLINE]

Chicoric acid binds to two sites and decreases the activity of the YopH bacterial virulence factor.

1 year 10 months ago
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Chicoric acid binds to two sites and decreases the activity of the YopH bacterial virulence factor.

Oncotarget. 2016 Jan 19;7(3):2229-38

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

Abstract
Chicoric acid (CA) is a phenolic compound present in dietary supplements with a large spectrum of biological properties reported ranging from antioxidant, to antiviral, to immunostimulatory properties. Due to the fact that chicoric acid promotes phagocytic activity and was reported as an allosteric inhibitor of the PTP1B phosphatase, we examined the effect of CA on YopH phosphatase from pathogenic bacteria, which block phagocytic processes of a host cell. We performed computational studies of chicoric acid binding to YopH as well as validation experiments with recombinant enzymes. In addition, we performed similar studies for caffeic and chlorogenic acids to compare the results. Docking experiments demonstrated that, from the tested compounds, only CA binds to both catalytic and secondary binding sites of YopH. Our experimental results showed that CA reduces activity of recombinant YopH phosphatase from Yersinia enterocolitica and human CD45 phosphatase. The inhibition caused by CA was irreversible and did not induce oxidation of catalytic cysteine. We proposed that inactivation of YopH induced by CA is involved with allosteric inhibition by interacting with essential regions responsible for ligand binding.

PMID: 26735581 [PubMed - indexed for MEDLINE]

Josephin Domain Structural Conformations Explored by Metadynamics in Essential Coordinates.

1 year 10 months ago
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Josephin Domain Structural Conformations Explored by Metadynamics in Essential Coordinates.

PLoS Comput Biol. 2016 Jan;12(1):e1004699

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

Abstract
The Josephin Domain (JD), i.e. the N-terminal domain of Ataxin 3 (At3) protein, is an interesting example of competition between physiological function and aggregation risk. In fact, the fibrillogenesis of Ataxin 3, responsible for the spinocerebbellar ataxia 3, is strictly related to the JD thermodynamic stability. Whereas recent NMR studies have demonstrated that different JD conformations exist, the likelihood of JD achievable conformational states in solution is still an open issue. Marked differences in the available NMR models are located in the hairpin region, supporting the idea that JD has a flexible hairpin in dynamic equilibrium between open and closed states. In this work we have carried out an investigation on the JD conformational arrangement by means of both classical molecular dynamics (MD) and Metadynamics employing essential coordinates as collective variables. We provide a representation of the free energy landscape characterizing the transition pathway from a JD open-like structure to a closed-like conformation. Findings of our in silico study strongly point to the closed-like conformation as the most likely for a Josephin Domain in water.

PMID: 26745628 [PubMed - indexed for MEDLINE]

Algebraic and topological indices of molecular pathway networks in human cancers.

1 year 10 months ago
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Algebraic and topological indices of molecular pathway networks in human cancers.

Math Biosci Eng. 2015 Dec;12(6):1289-302

Authors: Hinow P, Rietman EA, Omar SI, Tuszyński JA

Abstract
Protein-protein interaction networks associated with diseases have gained prominence as an area of research. We investigate algebraic and topological indices for protein-protein interaction networks of 11 human cancers derived from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. We find a strong correlation between relative automorphism group sizes and topological network complexities on the one hand and five year survival probabilities on the other hand. Moreover, we identify several protein families (e.g. PIK, ITG, AKT families) that are repeated motifs in many of the cancer pathways. Interestingly, these sources of symmetry are often central rather than peripheral. Our results can aide in identification of promising targets for anti-cancer drugs. Beyond that, we provide a unifying framework to study protein-protein interaction networks of families of related diseases (e.g. neurodegenerative diseases, viral diseases, substance abuse disorders).

PMID: 26775864 [PubMed - indexed for MEDLINE]

Synthesis, antiproliferative activity and molecular docking of Colchicine derivatives.

1 year 10 months ago
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Synthesis, antiproliferative activity and molecular docking of Colchicine derivatives.

Bioorg Chem. 2016 Feb;64:103-12

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

Abstract
In order to create more potent anticancer agents, a series of five structurally different derivatives of Colchicine have been synthesised. These compounds were characterised spectroscopically and structurally and their antiproliferative activity against four human tumour cell lines (HL-60, HL-60/vinc, LoVo, LoVo/DX) was evaluated. Additionally the activity of the studied compounds was calculated using computational methods involving molecular docking of the Colchicine derivatives to β-tubulin. The experimental and computational results are in very good agreement indicating that the antimitotic activity of Colchicine derivatives can be readily predicted using computational modeling methods.

PMID: 26794327 [PubMed - indexed for MEDLINE]

Characterization of the AXH domain of Ataxin-1 using enhanced sampling and functional mode analysis.

1 year 10 months ago
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Characterization of the AXH domain of Ataxin-1 using enhanced sampling and functional mode analysis.

Proteins. 2016 May;84(5):666-73

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

Abstract
Ataxin-1 is the protein responsible for the Spinocerebellar ataxia type 1, an incurable neurodegenerative disease caused by polyglutamine expansion. The AXH domain plays a pivotal role in physiological functions of Ataxin-1. In Spinocerebellar ataxia 1, the AXH domain is involved in the misfolding and aggregation pathway. Here molecular modeling is applied to investigate the protein-protein interactions contributing to the AXH dimer stability. Particular attention is focused on: (i) the characterization of AXH monomer-monomer interface; (ii) the molecular description of the AXH monomer-monomer interaction dynamics. Technically, an approach based on functional mode analysis, here applied to replica exchange molecular dynamics trajectories, was employed. The findings of this study are consistent with previous experimental results and elucidate the pivotal role of the I580 residue in mediating the AXH monomer-monomer interaction dynamics.

PMID: 26879337 [PubMed - indexed for MEDLINE]

Toward precision medicine of breast cancer.

1 year 10 months ago
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Toward precision medicine of breast cancer.

Theor Biol Med Model. 2016 Feb 29;13:7

Authors: Carels N, Spinassé LB, Tilli TM, Tuszynski JA

Abstract
In this review, we report on breast cancer's molecular features and on how high throughput technologies are helping in understanding the dynamics of tumorigenesis and cancer progression with the aim of developing precision medicine methods. We first address the current state of the art in breast cancer therapies and challenges in order to progress towards its cure. Then, we show how the interaction of high-throughput technologies with in silico modeling has led to set up useful inferences for promising strategies of target-specific therapies with low secondary effect incidence for patients. Finally, we discuss the challenge of pharmacogenetics in the clinical practice of cancer therapy. All these issues are explored within the context of precision medicine.

PMID: 26925829 [PubMed - indexed for MEDLINE]

New design of nucleotide excision repair (NER) inhibitors for combination cancer therapy.

1 year 10 months ago
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New design of nucleotide excision repair (NER) inhibitors for combination cancer therapy.

J Mol Graph Model. 2016 Apr;65:71-82

Authors: Gentile F, Tuszynski JA, Barakat KH

Abstract
Many cancer chemotherapy agents act by targeting the DNA of cancer cells, causing substantial damage within their genome and causing them to undergo apoptosis. An effective DNA repair pathway in cancer cells can act in a reverse way by removing these drug-induced DNA lesions, allowing cancer cells to survive, grow and proliferate. In this context, DNA repair inhibitors opened a new avenue in cancer treatment, by blocking the DNA repair mechanisms from removing the chemotherapy-mediated DNA damage. In particular, the nucleotide excision repair (NER) involves more than thirty protein-protein interactions and removes DNA adducts caused by platinum-based chemotherapy. The excision repair cross-complementation group 1 (ERCC1)-xeroderma pigmentosum, complementation group A (XPA) protein (XPA-ERCC1) complex seems to be one of the most promising targets in this pathway. ERCC1 is over expressed in cancer cells and the only known cellular function so far for XPA is to recruit ERCC1 to the damaged point. Here, we build upon our recent advances in identifying inhibitors for this interaction and continue our efforts to rationally design more effective and potent regulators for the NER pathway. We employed in silico drug design techniques to: (1) identify compounds similar to the recently discovered inhibitors, but more effective at inhibiting the XPA-ERCC1 interactions, and (2) identify different scaffolds to develop novel lead compounds. Two known inhibitor structures have been used as starting points for two ligand/structure-hybrid virtual screening approaches. The findings described here form a milestone in discovering novel inhibitors for the NER pathway aiming at improving the efficacy of current platinum-based therapy, by modulating the XPA-ERCC1 interaction.

PMID: 26939044 [PubMed - indexed for MEDLINE]

A physiologically-based flow network model for hepatic drug elimination III: 2D/3D DLA lobule models.

1 year 10 months ago
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A physiologically-based flow network model for hepatic drug elimination III: 2D/3D DLA lobule models.

Theor Biol Med Model. 2016 Mar 03;13:9

Authors: Rezania V, Coombe D, Tuszynski JA

Abstract
BACKGROUND: One of the major issues in current pharmaceutical development is potential hepatotoxicity and drug-induced liver damage. This is due to the unique metabolic processes performed in the liver to prevent accumulation of a wide range of chemicals in the blood. Recently, we developed a physiologically-based lattice model to address the transport and metabolism of drugs in the liver lobule (liver functional unit).
METHOD: In this paper, we extend our idealized model to consider structural and spatial variability in two and three dimensions. We introduce a hexagonal-based model with one input (portal vein) and six outputs (hepatic veins) to represent a typical liver lobule. To capture even more realistic structures, we implement a novel sequential diffusion-limited aggregation (DLA) method to construct a morphological sinusoid network in the lobule. A 3D model constructed with stacks of multiple 2D sinusoid realizations is explored to study the effects of 3D structural variations. The role of liver zonation on drug metabolism in the lobule is also addressed, based on flow-based predicted steady-state O2 profiles used as a zonation indicator.
RESULTS: With this model, we analyze predicted drug concentration levels observed exiting the lobule with their detailed distribution inside the lobule, and compare with our earlier idealized models. In 2D, due to randomness of the sinusoidal structure, individual hepatic veins respond differently (i.e. at different times) to injected drug. In 3D, however, the variation of response to the injected drug is observed to be less extreme. Also, the production curves show more diffusive behavior in 3D than in 2D.
CONCLUSION: Although, the individual producing ports respond differently, the average lobule production summed over all hepatic veins is more diffuse. Thus the net effect of all these variations makes the overall response smoother. We also show that, in 3D, the effect of zonation on drug production characteristics appears quite small. Our new biophysical structural analysis of a physiologically-based 3D lobule can therefore form the basis for a quantitative assessment of liver function and performance both in health and disease.

PMID: 26939615 [PubMed - indexed for MEDLINE]

Screening Anti-Cancer Drugs against Tubulin using Catch-and-Release Electrospray Ionization Mass Spectrometry.

1 year 10 months ago
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Screening Anti-Cancer Drugs against Tubulin using Catch-and-Release Electrospray Ionization Mass Spectrometry.

J Am Soc Mass Spectrom. 2016 May;27(5):876-85

Authors: Rezaei Darestani R, Winter P, Kitova EN, Tuszynski JA, Klassen JS

Abstract
Tubulin, which is the building block of microtubules, plays an important role in cell division. This critical role makes tubulin an attractive target for the development of chemotherapeutic drugs to treat cancer. Currently, there is no general binding assay for tubulin-drug interactions. The present work describes the application of the catch-and-release electrospray ionization mass spectrometry (CaR-ESI-MS) assay to investigate the binding of colchicinoid drugs to αβ-tubulin dimers extracted from porcine brain. Proof-of-concept experiments using positive (ligands with known affinities) and negative (non-binders) controls were performed to establish the reliability of the assay. The assay was then used to screen a library of seven colchicinoid analogues to test their binding to tubulin and to rank their affinities.

PMID: 26944280 [PubMed - indexed for MEDLINE]