A physiologically-based flow network model for hepatic drug elimination I: regular lattice lobule model.

1 year 10 months ago
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A physiologically-based flow network model for hepatic drug elimination I: regular lattice lobule model.

Theor Biol Med Model. 2013 Sep 05;10:52

Authors: Rezania V, Marsh R, Coombe D, Tuszynski J

Abstract
We develop a physiologically-based lattice model for the transport and metabolism of drugs in the functional unit of the liver, called the lobule. In contrast to earlier studies, we have emphasized the dominant role of convection in well-vascularized tissue with a given structure. Estimates of convective, diffusive and reaction contributions are given. We have compared drug concentration levels observed exiting the lobule with their predicted detailed distribution inside the lobule, assuming that most often the former is accessible information while the latter is not.

PMID: 24007328 [PubMed - indexed for MEDLINE]

A physiologically-based flow network model for hepatic drug elimination II: variable lattice lobule models.

1 year 10 months ago
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A physiologically-based flow network model for hepatic drug elimination II: variable lattice lobule models.

Theor Biol Med Model. 2013 Sep 05;10:53

Authors: Rezania V, Marsh R, Coombe D, Tuszynski J

Abstract
We extend a physiologically-based lattice model for the transport and metabolism of drugs in the liver lobule (liver functional unit) to consider structural and spatial variability. We compare predicted drug concentration levels observed exiting the lobule with their detailed distribution inside the lobule, and indicate the role that structural variation has on these results. Liver zonation and its role on drug metabolism represent another aspect of structural inhomogeneity that we consider here. Since various liver diseases can be thought to produce such structural variations, our analysis gives insight into the role of disease on liver function and performance. These conclusions are based on the dominant role of convection in well-vascularized tissue with a given structure.

PMID: 24007357 [PubMed - indexed for MEDLINE]

Near death experiences: a multidisciplinary hypothesis.

1 year 10 months ago
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Near death experiences: a multidisciplinary hypothesis.

Front Hum Neurosci. 2013;7:533

Authors: Bókkon I, Mallick BN, Tuszynski JA

Abstract
Recently, we proposed a novel biophysical concept regarding on the appearance of brilliant lights during near death experiences (NDEs) (Bókkon and Salari, 2012). Specifically, perceiving brilliant light in NDEs has been proposed to arise due to the reperfusion that produces unregulated overproduction of free radicals and energetically excited molecules that can generate a transient enhancement of bioluminescent biophotons in different areas of the brain, including retinotopic visual areas. If this excess of bioluminescent photon emission exceeds a threshold in retinotopic visual areas, this can appear as (phosphene) lights because the brain interprets these intrinsic retinotopic bioluminescent photons as if they originated from the external physical world. Here, we review relevant literature that reported experimental studies (Imaizumi et al., 1984; Suzuki et al., 1985) that essentially support our previously published conception, i.e., that seeing lights in NDEs may be due to the transient enhancement of bioluminescent biophotons. Next, we briefly describe our biophysical visual representation model that may explain brilliant lights experienced during NDEs (by phosphenes as biophotons) and REM sleep associated dream-like intrinsic visual imageries through biophotons in NDEs. Finally, we link our biophysical visual representation notion to self-consciousness that may involve extremely low-energy quantum entanglements. This article is intended to introduce novel concepts for discussion and does not pretend to give the ultimate explanation for the currently unanswerable questions about matter, life and soul; their creation and their interrelationship.

PMID: 24062655 [PubMed]

A computational model for overcoming drug resistance using selective dual-inhibitors for aurora kinase A and its T217D variant.

1 year 10 months ago
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A computational model for overcoming drug resistance using selective dual-inhibitors for aurora kinase A and its T217D variant.

Mol Pharm. 2013 Dec 02;10(12):4572-89

Authors: Barakat KH, Huzil JT, Jordan KE, Evangelinos C, Houghton M, Tuszynski J

Abstract
The human Aurora kinase-A (AK-A) is an essential mitotic regulator that is frequently overexpressed in several cancers. The recent development of several novel AK-A inhibitors has been driven by the well-established association of this target with cancer development and progression. However, resistance and cross-reactivity with similar kinases demands an improvement in our understanding of key molecular interactions between the Aurora kinase-A substrate binding pocket and potential inhibitors. Here, we describe the implementation of state-of-the-art virtual screening techniques to discover a novel set of Aurora kinase-A ligands that are predicted to strongly bind not only to the wild type protein, but also to the T217D mutation that exhibits resistance to existing inhibitors. Furthermore, a subset of these computationally screened ligands was shown to be more selective toward the mutant variant over the wild type protein. The description of these selective subsets of ligands provides a unique pharmacological tool for the design of new drug regimens aimed at overcoming both kinase cross-reactivity and drug resistance associated with the Aurora kinase-A T217D mutation.

PMID: 24094068 [PubMed - indexed for MEDLINE]

Detailed computational study of the active site of the hepatitis C viral RNA polymerase to aid novel drug design.

1 year 10 months ago
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Detailed computational study of the active site of the hepatitis C viral RNA polymerase to aid novel drug design.

J Chem Inf Model. 2013 Nov 25;53(11):3031-43

Authors: Barakat KH, Law J, Prunotto A, Magee WC, Evans DH, Tyrrell DL, Tuszynski J, Houghton M

Abstract
The hepatitis C virus (HCV) RNA polymerase, NS5B, is a leading target for novel and selective HCV drug design. The enzyme has been the subject of intensive drug discovery aimed at developing direct acting antiviral (DAA) agents that inhibit its activity and hence prevent the virus from replicating its genome. In this study, we focus on one class of NS5B inhibitors, namely nucleos(t)ide mimetics. Forty-one distinct nucleotide structures have been modeled within the active site of NS5B for the six major HCV genotypes. Our comprehensive modeling protocol employed 287 different molecular dynamics simulations combined with the molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) methodology to rank and analyze these structures for all genotypes. The binding interactions of the individual compounds have been investigated and reduced to the atomic level. The present study significantly refines our understanding of the mode of action of NS5B-nucleotide-inhibitors, identifies the key structural elements necessary for their activity, and implements the tools for ranking the potential of additional much needed novel inhibitors of NS5B.

PMID: 24116674 [PubMed - indexed for MEDLINE]

Bridging the gap between the technological singularity and mainstream medicine: highlighting a course on technology and the future of medicine.

1 year 10 months ago
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Bridging the gap between the technological singularity and mainstream medicine: highlighting a course on technology and the future of medicine.

Glob J Health Sci. 2013 Sep 09;5(6):112-25

Authors: Solez K, Bernier A, Crichton J, Graves H, Kuttikat P, Lockwood R, Marovitz WF, Monroe D, Pallen M, Pandya S, Pearce D, Saleh A, Sandhu N, Sergi C, Tuszynski J, Waugh E, White J, Woodside M, Wyndham R, Zaiane O, Zakus D

Abstract
The "technological singularity" is defined as that putative point in time forecasted to occur in the mid twenty-first century when machines will become smarter than humans, leading humans and machines to merge. It is hypothesized that this event will have a profound influence on medicine and population health. This work describes a new course on Technology and the Future of Medicine developed by a diverse, multi-disciplinary group of faculty members at a Canadian university. The course began as a continuous professional learning course and was later established as a recognized graduate course. We describe the philosophy of the course, the barriers encountered in course development, and some of the idiosyncratic solutions that were developed to overcome these, including the use of YouTube audience retention analytics. We hope that this report might provide a useful template for other institutions attempting to set up similar programs.

PMID: 24171879 [PubMed - indexed for MEDLINE]

An accurate method for prediction of protein-ligand binding site on protein surface using SVM and statistical depth function.

1 year 10 months ago
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An accurate method for prediction of protein-ligand binding site on protein surface using SVM and statistical depth function.

Biomed Res Int. 2013;2013:409658

Authors: Wang K, Gao J, Shen S, Tuszynski JA, Ruan J, Hu G

Abstract
Since proteins carry out their functions through interactions with other molecules, accurately identifying the protein-ligand binding site plays an important role in protein functional annotation and rational drug discovery. In the past two decades, a lot of algorithms were present to predict the protein-ligand binding site. In this paper, we introduce statistical depth function to define negative samples and propose an SVM-based method which integrates sequence and structural information to predict binding site. The results show that the present method performs better than the existent ones. The accuracy, sensitivity, and specificity on training set are 77.55%, 56.15%, and 87.96%, respectively; on the independent test set, the accuracy, sensitivity, and specificity are 80.36%, 53.53%, and 92.38%, respectively.

PMID: 24195070 [PubMed - indexed for MEDLINE]

A computationally designed DNA aptamer template with specific binding to phosphatidylserine.

1 year 10 months ago
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A computationally designed DNA aptamer template with specific binding to phosphatidylserine.

Nucleic Acid Ther. 2013 Dec;23(6):418-26

Authors: Ashrafuzzaman M, Tseng CY, Kapty J, Mercer JR, Tuszynski JA

Abstract
The phospholipid phosphatidylserine (PS) is an early marker exploited for detecting apoptosis (PS externalization in the cell membrane bilayer) and one factor that is associated with increased amyloid plaque deposition in transmissible spongiform encephalopathies (TSEs). PS can therefore be considered as a promising target for diagnosis or treatment of diseases. Aptamers (short nucleic acid sequences) are a particularly attractive class of materials among those currently considered for targeting PS. Here we applied an entropy based seed-and-grow strategy to design a DNA aptamer template to bind specifically to PS. The binding properties of designed aptamers were investigated computationally and experimentally. The studies identify the sequence, 5'-AAAGAC-3', as the preferred template for further modifications and studies toward its practical implementations.

PMID: 24279298 [PubMed - indexed for MEDLINE]

Homology and molecular dynamics models of toll-like receptor 7 protein and its dimerization.

1 year 10 months ago
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Homology and molecular dynamics models of toll-like receptor 7 protein and its dimerization.

Chem Biol Drug Des. 2014 Jun;83(6):656-65

Authors: Tseng CY, Gajewski M, Danani A, Tuszynski JA

Abstract
Toll-like receptor protein 7 is a transmembrane protein playing a crucial role in the signaling pathways involved in innate immunity. Its crystal structure is not yet available, but there are several proteins possessing domains of sufficiently high homology, which enabled us to build a model of the toll-like receptor protein 7 monomer and gain insights into dimer formation. To obtain a reliable structure prediction, we subjected this model to equilibration using molecular dynamics simulations. Furthermore, the equilibrated monomer structure was used to construct models of dimerization and to predict binding sites for small ligands. Docking studies were performed for some of the known toll-like receptor protein 7 ligands. We determined that a new homology model generated by the LOOPP server provides a good alternative to a previously reported model. Our docking results indicate that the addition of either imiquimod or 1V209 to a toll-like receptor protein 7 dimer changes an unfavorable interaction into a favorable one. We found that eight small molecules docked to two pockets in toll-like receptor protein 7 bind to both pockets at pH 7 and at pH 5.5. This work provides a realistic model that could be used for drug discovery aimed at finding toll-like receptor protein 7 dimerization activators, with potential clinical applications to a host of diseases, including cancer.

PMID: 24406029 [PubMed - indexed for MEDLINE]

Systematic identification and evolutionary analysis of catalytically versatile cytochrome p450 monooxygenase families enriched in model basidiomycete fungi.

1 year 10 months ago
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Systematic identification and evolutionary analysis of catalytically versatile cytochrome p450 monooxygenase families enriched in model basidiomycete fungi.

PLoS One. 2014;9(1):e86683

Authors: Syed K, Shale K, Pagadala NS, Tuszynski J

Abstract
Genome sequencing of basidiomycetes, a group of fungi capable of degrading/mineralizing plant material, revealed the presence of numerous cytochrome P450 monooxygenases (P450s) in their genomes, with some exceptions. Considering the large repertoire of P450s found in fungi, it is difficult to identify P450s that play an important role in fungal metabolism and the adaptation of fungi to diverse ecological niches. In this study, we followed Sir Charles Darwin's theory of natural selection to identify such P450s in model basidiomycete fungi showing a preference for different types of plant components degradation. Any P450 family comprising a large number of member P450s compared to other P450 families indicates its natural selection over other P450 families by its important role in fungal physiology. Genome-wide comparative P450 analysis in the basidiomycete species, Phanerochaete chrysosporium, Phanerochaete carnosa, Agaricus bisporus, Postia placenta, Ganoderma sp. and Serpula lacrymans, revealed enrichment of 11 P450 families (out of 68 P450 families), CYP63, CYP512, CYP5035, CYP5037, CYP5136, CYP5141, CYP5144, CYP5146, CYP5150, CYP5348 and CYP5359. Phylogenetic analysis of the P450 family showed species-specific alignment of P450s across the P450 families with the exception of P450s of Phanerochaete chrysosporium and Phanerochaete carnosa, suggesting paralogous evolution of P450s in model basidiomycetes. P450 gene-structure analysis revealed high conservation in the size of exons and the location of introns. P450s with the same gene structure were found tandemly arranged in the genomes of selected fungi. This clearly suggests that extensive gene duplications, particularly tandem gene duplications, led to the enrichment of selective P450 families in basidiomycetes. Functional analysis and gene expression profiling data suggest that members of the P450 families are catalytically versatile and possibly involved in fungal colonization of plant material. To our knowledge, this is the first report on the identification and comparative-evolutionary analysis of P450 families enriched in model basidiomycetes.

PMID: 24466198 [PubMed - indexed for MEDLINE]

Regulation of channel function due to physical energetic coupling with a lipid bilayer.

1 year 10 months ago
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Regulation of channel function due to physical energetic coupling with a lipid bilayer.

Biochem Biophys Res Commun. 2014 Mar 07;445(2):463-8

Authors: Ashrafuzzaman M, Tseng CY, Tuszynski JA

Abstract
Regulation of membrane protein functions due to hydrophobic coupling with a lipid bilayer has been investigated. An energy formula describing interactions between lipid bilayer and integral ion channels with different structures, which is based on the screened Coulomb interaction approximation, has been developed. Here the interaction energy is represented as being due to charge-based interactions between channel and lipid bilayer. The hydrophobic bilayer thickness channel length mismatch is found to induce channel destabilization exponentially while negative lipid curvature linearly. Experimental parameters related to channel dynamics are consistent with theoretical predictions. To measure comparable energy parameters directly in the system and to elucidate the mechanism at an atomistic level we performed molecular dynamics (MD) simulations of the ion channel forming peptide-lipid complexes. MD simulations indicate that peptides and lipids experience electrostatic and van der Waals interactions for short period of time when found within each other's proximity. The energies from these two interactions are found to be similar to the energies derived theoretically using the screened Coulomb and the van der Waals interactions between peptides (in ion channel) and lipids (in lipid bilayer) due to mainly their charge properties. The results of in silico MD studies taken together with experimental observable parameters and theoretical energetic predictions suggest that the peptides induce ion channels inside lipid membranes due to peptide-lipid physical interactions. This study provides a new insight helping better understand of the underlying mechanisms of membrane protein functions in cell membrane leading to important biological implications.

PMID: 24530910 [PubMed - indexed for MEDLINE]

A Refined Model of the HCV NS5A protein bound to daclatasvir explains drug-resistant mutations and activity against divergent genotypes.

1 year 10 months ago
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A Refined Model of the HCV NS5A protein bound to daclatasvir explains drug-resistant mutations and activity against divergent genotypes.

J Chem Inf Model. 2015 Feb 23;55(2):362-73

Authors: Barakat KH, Anwar-Mohamed A, Tuszynski JA, Robins MJ, Tyrrell DL, Houghton M

Abstract
Many direct-acting antiviral agents (DAAs) that selectively block hepatitis C virus (HCV) replication are currently under development. Among these agents is Daclatasvir, a first-in-class inhibitor targeting the NS5A viral protein. Although Daclatasvir is the most potent HCV antiviral molecule yet developed, its binding location and mode of binding remain unknown. The drug exhibits a low barrier to resistance mutations, particularly in genotype 1 viruses, but its efficacy against other genotypes is unclear. Using state-of-the-art modeling techniques combined with the massive computational power of Blue Gene/Q, we identified the atomic interactions of Daclatasvir within NS5A for different HCV genotypes and for several reported resistant mutations. The proposed model is the first to reveal the detailed binding mode of Daclatasvir. It also provides a tool to facilitate design of second generation drugs, which may confer less resistance and/or broader activity against HCV.

PMID: 24730573 [PubMed - indexed for MEDLINE]

Quantum effects in the understanding of consciousness.

1 year 10 months ago
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Quantum effects in the understanding of consciousness.

J Integr Neurosci. 2014 Jun;13(2):229-52

Authors: Hameroff SR, Craddock TJ, Tuszynski JA

Abstract
This paper presents a historical perspective on the development and application of quantum physics methodology beyond physics, especially in biology and in the area of consciousness studies. Quantum physics provides a conceptual framework for the structural aspects of biological systems and processes via quantum chemistry. In recent years individual biological phenomena such as photosynthesis and bird navigation have been experimentally and theoretically analyzed using quantum methods building conceptual foundations for quantum biology. Since consciousness is attributed to human (and possibly animal) mind, quantum underpinnings of cognitive processes are a logical extension. Several proposals, especially the Orch OR hypothesis, have been put forth in an effort to introduce a scientific basis to the theory of consciousness. At the center of these approaches are microtubules as the substrate on which conscious processes in terms of quantum coherence and entanglement can be built. Additionally, Quantum Metabolism, quantum processes in ion channels and quantum effects in sensory stimulation are discussed in this connection. We discuss the challenges and merits related to quantum consciousness approaches as well as their potential extensions.

PMID: 25012711 [PubMed - indexed for MEDLINE]

Keeping time: could quantum beating in microtubules be the basis for the neural synchrony related to consciousness?

1 year 10 months ago
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Keeping time: could quantum beating in microtubules be the basis for the neural synchrony related to consciousness?

J Integr Neurosci. 2014 Jun;13(2):293-311

Authors: Craddock TJ, Priel A, Tuszynski JA

Abstract
This paper discusses the possibility of quantum coherent oscillations playing a role in neuronal signaling. Consciousness correlates strongly with coherent neural oscillations, however the mechanisms by which neurons synchronize are not fully elucidated. Recent experimental evidence of quantum beats in light-harvesting complexes of plants (LHCII) and bacteria provided a stimulus for seeking similar effects in important structures found in animal cells, especially in neurons. We argue that microtubules (MTs), which play critical roles in all eukaryotic cells, possess structural and functional characteristics that are consistent with quantum coherent excitations in the aromatic groups of their tryptophan residues. Furthermore we outline the consequences of these findings on neuronal processes including the emergence of consciousness.

PMID: 25012713 [PubMed - indexed for MEDLINE]

A simple method for finding a protein's ligand-binding pockets.

1 year 10 months ago
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A simple method for finding a protein's ligand-binding pockets.

BMC Struct Biol. 2014 Jul 19;14:18

Authors: Saberi Fathi SM, Tuszynski JA

Abstract
BACKGROUND: This paper provides a simple and rapid method for a protein-clustering strategy. The basic idea implemented here is to use computational geometry methods to predict and characterize ligand-binding pockets of a given protein structure. In addition to geometrical characteristics of the protein structure, we consider some simple biochemical properties that help recognize the best candidates for pockets in a protein's active site.
RESULTS: Our results are shown to produce good agreement with known empirical results.
CONCLUSIONS: The method presented in this paper is a low-cost rapid computational method that could be used to classify proteins and other biomolecules, and furthermore could be useful in reducing the cost and time of drug discovery.

PMID: 25038637 [PubMed - indexed for MEDLINE]

In silico studies and fluorescence binding assays of potential anti-prion compounds reveal an important binding site for prion inhibition from PrP(C) to PrP(Sc).

1 year 10 months ago
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In silico studies and fluorescence binding assays of potential anti-prion compounds reveal an important binding site for prion inhibition from PrP(C) to PrP(Sc).

Eur J Med Chem. 2015 Feb 16;91:118-31

Authors: Pagadala NS, Perez-Pineiro R, Wishart DS, Tuszynski JA

Abstract
To understand the pharmacophore properties of 2-aminothiazoles and design novel inhibitors against the prion protein, a highly predictive 3D quantitative structure-activity relationship (QSAR) has been developed by performing comparative molecular field analysis (CoMFA) and comparative similarity analysis (CoMSIA). Both CoMFA and CoMSIA maps reveal the presence of the oxymethyl groups in meta and para positions on the phenyl ring of compound 17 (N-[4-(3,4-dimethoxyphenyl)-1,3-thiazol-2-yl]quinolin-2-amine), is necessary for activity while electro-negative nitrogen of quinoline is highly favorable to enhance activity. The blind docking results for these compounds show that the compound with quinoline binds with higher affinity than isoquinoline and naphthalene groups. Out of 150 novel compounds retrieved using finger print analysis by pharmacophoric model predicted based on five test sets of compounds, five compounds with diverse scaffolds were selected for biological evaluation as possible PrP inhibitors. Molecular docking combined with fluorescence quenching studies show that these compounds bind to pocket-D of SHaPrP near Trp145. The new antiprion compounds 3 and 6, which bind with the interaction energies of -12.1 and -13.2 kcal/mol, respectively, show fluorescence quenching with binding constant (Kd) values of 15.5 and 44.14 μM, respectively. Further fluorescence binding assays with compound 5, which is similar to 2-aminothiazole as a positive control, also show that the molecule binds to the pocket-D with the binding constant (Kd) value of 84.7 μM. Finally, both molecular docking and a fluorescence binding assay of noscapine as a negative control reveals the same binding site on the surface of pocket-A near a rigid loop between β2 and α2 interacting with Arg164. This high level of correlation between molecular docking and fluorescence quenching studies confirm that these five compounds are likely to act as inhibitors for prion propagation while noscapine might act as a prion accelerator from PrP(C) to PrP(Sc).

PMID: 25042003 [PubMed - indexed for MEDLINE]

Geometrical comparison of two protein structures using Wigner-D functions.

1 year 10 months ago
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Geometrical comparison of two protein structures using Wigner-D functions.

Proteins. 2014 Oct;82(10):2756-69

Authors: Saberi Fathi SM, White DT, Tuszynski JA

Abstract
In this article, we develop a quantitative comparison method for two arbitrary protein structures. This method uses a root-mean-square deviation characterization and employs a series expansion of the protein's shape function in terms of the Wigner-D functions to define a new criterion, which is called a "similarity value." We further demonstrate that the expansion coefficients for the shape function obtained with the help of the Wigner-D functions correspond to structure factors. Our method addresses the common problem of comparing two proteins with different numbers of atoms. We illustrate it with a worked example.

PMID: 25043646 [PubMed - indexed for MEDLINE]

Analysis of the strength of interfacial hydrogen bonds between tubulin dimers using quantum theory of atoms in molecules.

1 year 10 months ago
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Analysis of the strength of interfacial hydrogen bonds between tubulin dimers using quantum theory of atoms in molecules.

Biophys J. 2014 Aug 05;107(3):740-750

Authors: Ayoub AT, Craddock TJA, Klobukowski M, Tuszynski J

Abstract
Microtubules are key structural elements that, among numerous biological functions, maintain the cytoskeleton of the cell and have a major role in cell division, which makes them important cancer chemotherapy targets. Understanding the energy balance that brings tubulin dimers, the building blocks of microtubules, together to form a microtubule is especially important for revealing the mechanism of their dynamic instability. Several studies have been conducted to estimate various contributions to the free energy of microtubule formation. However, the hydrogen-bond contribution was not studied before as a separate component. In this work, we use concepts such as the quantum theory of atoms in molecules to estimate the per-residue strength of hydrogen bonds contributing to the overall stability that brings subunits together in pair of tubulin heterodimers, across both the longitudinal and lateral interfaces. Our study shows that hydrogen bonding plays a major role in the stability of tubulin systems. Several residues that are crucial to the binding of vinca alkaloids are shown to be strongly involved in longitudinal microtubule stabilization. This indicates a direct relation between the binding of these agents and the effect on the interfacial hydrogen-bonding network, and explains the mechanism of their action. Lateral contacts showed much higher stability than longitudinal ones (-462 ± 70 vs. -392 ± 59 kJ/mol), which suggests a dramatic lateral stabilization effect of the GTP cap in the β-subunit. The role of the M-loop in lateral stability in absence of taxol was shown to be minor. The B-lattice lateral hydrogen bonds are shown to be comparable in strength to the A-lattice ones (-462 ± 70 vs. -472 ± 46 kJ/mol). These findings establish the importance of hydrogen bonds to the stability of tubulin systems.

PMID: 25099813 [PubMed - indexed for MEDLINE]

A human ether-á-go-go-related (hERG) ion channel atomistic model generated by long supercomputer molecular dynamics simulations and its use in predicting drug cardiotoxicity.

1 year 10 months ago
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A human ether-á-go-go-related (hERG) ion channel atomistic model generated by long supercomputer molecular dynamics simulations and its use in predicting drug cardiotoxicity.

Toxicol Lett. 2014 Nov 04;230(3):382-92

Authors: Anwar-Mohamed A, Barakat KH, Bhat R, Noskov SY, Tyrrell DL, Tuszynski JA, Houghton M

Abstract
Acquired cardiac long QT syndrome (LQTS) is a frequent drug-induced toxic event that is often caused through blocking of the human ether-á-go-go-related (hERG) K(+) ion channel. This has led to the removal of several major drugs post-approval and is a frequent cause of termination of clinical trials. We report here a computational atomistic model derived using long molecular dynamics that allows sensitive prediction of hERG blockage. It identified drug-mediated hERG blocking activity of a test panel of 18 compounds with high sensitivity and specificity and was experimentally validated using hERG binding assays and patch clamp electrophysiological assays. The model discriminates between potent, weak, and non-hERG blockers and is superior to previous computational methods. This computational model serves as a powerful new tool to predict hERG blocking thus rendering drug development safer and more efficient. As an example, we show that a drug that was halted recently in clinical development because of severe cardiotoxicity is a potent inhibitor of hERG in two different biological assays which could have been predicted using our new computational model.

PMID: 25127758 [PubMed - indexed for MEDLINE]