scholarly journals Integration of phylogenomics and molecular modeling reveals lineage-specific diversification of toxins in scorpions

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e5902 ◽  
Author(s):  
Carlos E. Santibáñez-López ◽  
Ricardo Kriebel ◽  
Jesús A. Ballesteros ◽  
Nathaniel Rush ◽  
Zachary Witter ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Calcium Channel ◽  
The Other ◽  
Phylogenetic Hypothesis ◽  
Molecular Models ◽  
Biological Targets ◽  
Genomic Resources ◽  
Taxonomic Sampling ◽  
Phylogenetic Inertia ◽  
Genome Scale

Scorpions have evolved a variety of toxins with a plethora of biological targets, but characterizing their evolution has been limited by the lack of a comprehensive phylogenetic hypothesis of scorpion relationships grounded in modern, genome-scale datasets. Disagreements over scorpion higher-level systematics have also incurred challenges to previous interpretations of venom families as ancestral or derived. To redress these gaps, we assessed the phylogenomic relationships of scorpions using the most comprehensive taxonomic sampling to date. We surveyed genomic resources for the incidence of calcins (a type of calcium channel toxin), which were previously known only from 16 scorpion species. Here, we show that calcins are diverse, but phylogenetically restricted only to parvorder Iurida, one of the two basal branches of scorpions. The other branch of scorpions, Buthida, bear the related LKTx toxins (absent in Iurida), but lack calcins entirely. Analysis of sequences and molecular models demonstrates remarkable phylogenetic inertia within both calcins and LKTx genes. These results provide the first synapomorphies (shared derived traits) for the recently redefined clades Buthida and Iurida, constituting the only known case of such traits defined from the morphology of molecules.

An Overview on Estimation of Lacidipine from Bulk and Formulation

2021 ◽  
pp. 223-226
Author(s):  
Nachiket S. Dighe ◽  
Mayur Bhosale ◽  
Pallavi B. Gaikwad
Keyword(s):  
Calcium Channel ◽  
Calcium Channel Blocker ◽  
Cardiac Arrhythmia ◽  
Channel Blocker ◽  
The Other

Lacidipine is a calcium channel blocker used in treatment of cardiac arrhythmia. Several methods had been reported for the estimation of lacidipine from bulk and formulations. Here in this an attempt is made to summarize the different methods used along with their specifications. Every method reported for the analysis had its own advantages over the other methods. As per the industrial scalability HPLC is the most useful and effective method for the estimation of Lacidipine from bulk and formulations.

Two calcium channels in basolateral membranes of rabbit ileal epithelial cells

1989 ◽  
Vol 257 (1) ◽  
pp. G86-G93
Author(s):  
F. R. Homaidan ◽  
M. Donowitz ◽  
G. A. Weiland ◽  
G. W. Sharp
Keyword(s):  
Epithelial Cells ◽  
Calcium Channels ◽  
Calcium Channel ◽  
Short Circuit ◽  
Short Circuit Current ◽  
The Other ◽  
Channel Blockers ◽  
Binding Studies ◽  
Rabbit Ileum ◽  
Basolateral Membranes

The actions of three different types of calcium channel blockers on short-circuit current (Isc) in rabbit ileum were studied. These included the phenylalkylamines, verapamil and (l)-desmethoxyverapamil (D888); the dihydropyridines, nifedipine and nitrendipine; and the benzothiazepine, diltiazem. All of the drugs decreased Isc, a change associated with increased Na and Cl absorption. Verapamil and D888 had the largest effects. The dihydropyridine, BAY K 8644, a calcium channel activator, increased Isc and decreased Na and Cl absorption, effects not inhibited by tetrodotoxin. The phenylalkylamines had an additional effect on Isc in the presence of a maximally inhibitory concentration of the dihydropyridines, suggesting the possibility of two distinct calcium channels, one of which is the L-type voltage-activated, dihydropyridine- and phenylalkylamine-sensitive channel, and the other is a channel only sensitive to phenylalkylamines but not to dihydropyridines. [3H]nitrendipine and [3H]D888 binding to an enriched preparation of basolateral membranes from ileal epithelial cells was characterized. Each ligand bound specifically and saturably to an apparently single population of high-affinity sites with [3H]D888 having three times as many binding sites as [3H]nitrendipine. [3H]nitrendipine binding was partially inhibited by verapamil and D888 and was increased by diltiazem; whereas [3H]D888 binding was inhibited completely by verapamil but only partially by nitrendipine and diltiazem. These transport and binding studies suggest the presence of two types of Ca2+ channels in ileal epithelial cells, one of which interacts with the dihydropyridines, the phenylalkylamines, and the benzothiazepines at three different sites and the other channel that only binds the phenylalkylamines.

scholarly journals Development and Validation of a Virtual Gelatin Model Using Molecular Modeling Computational Tools

Molecules ◽  
2019 ◽  
Vol 24 (18) ◽  
pp. 3365 ◽  
Author(s):  
Lukasz Radosinski ◽  
Karolina Labus ◽  
Piotr Zemojtel ◽  
Jakub W. Wojciechowski
Keyword(s):  
Molecular Dynamics ◽  
Molecular Modeling ◽  
Computational Design ◽  
Molecular Models ◽  
Fractional Free Volume ◽  
Computational Tools ◽  
Solubility Coefficient ◽  
Experimental Values ◽  
Development And Validation ◽  
Hansen Solubility

To successfully design and optimize the application of hydrogel matrices one has to effectively combine computational design tools with experimental methods. In this context, one of the most promising techniques is molecular modeling, which requires however accurate molecular models representing the investigated material. Although this method has been successfully used over the years for predicting the properties of polymers, its application to biopolymers, including gelatin, is limited. In this paper we provide a method for creating an atomistic representation of gelatin based on the modified FASTA codes of natural collagen. We show that the model created in this manner reproduces known experimental values of gelatin properties like density, glass-rubber transition temperature, WAXS profile and isobaric thermal expansion coefficient. We also present that molecular dynamics using the INTERFACE force field provides enough accuracy to track changes of density, fractional free volume and Hansen solubility coefficient over a narrow temperature regime (273–318 K) with 1 K accuracy. Thus we depict that using molecular dynamics one can predict properties of gelatin biopolymer as an efficient matrix for immobilization of various bioactive compounds, including enzymes.

Praziquantel and the benzodiazepine Ro 11-3128 do not compete for the same binding sites in schistosomes

Parasitology ◽  
2007 ◽  
Vol 135 (1) ◽  
pp. 47-54 ◽  
Author(s):  
L. PICA-MATTOCCIA ◽  
A. RUPPEL ◽  
C. M. XIA ◽  
D. CIOLI
Keyword(s):  
Calcium Channel ◽  
Binding Sites ◽  
Calcium Influx ◽  
Cytochalasin D ◽  
The Other ◽  
Channel Blockers ◽  
Spastic Paralysis ◽  
Receptor Sites

SUMMARYThe benzodiazepine Ro 11-3128 (methyl-clonazepam) presents several similarities with praziquantel with regard to its anti-schistosomal mode of action, since both drugs cause spastic paralysis, calcium influx and tegumental disruption in the parasites. In order to know whether the two compounds share the same binding sites in the schistosomes, we performed in vivo and in vitro competition experiments. We took advantage of the fact that Ro 11-3128 is active against immature Schistosoma mansoni (whereas praziquantel is inactive), and praziquantel is active against S. japonicum (which is insensitive to Ro 11-3128). An excess of praziquantel did not inhibit the activity of Ro 11-3128 against immature S. mansoni and an excess of Ro 11-3128 did not inhibit the activity of praziquantel against S. japonicum, suggesting that the schistosome binding sites of the two drugs are different. On the other hand, cytochalasin D, an agent known to perturb – among other things – calcium channel function, was capable of inhibiting the schistosomicidal activity of both praziquantel and Ro 11-3128, thus adding another element of similarity between the two anti-schistosomal agents. A similar, albeit partial, inhibition of the schistosomicidal activity of the two drugs was exerted by some of the classical calcium channel blockers. Taken together, these results suggest that praziquantel and Ro 11-3128, although binding to different schistosome receptor sites, may use the same basic anti-schistosomal effector mechanisms.

Glutamate Release by Osteoblasts in the Presence of Ionic Products from Bioactive Glass 60S

2005 ◽  
Vol 284-286 ◽  
pp. 537-540
Author(s):  
Patricia Valério ◽  
C.C.P. Mendes ◽  
Marivalda Pereira ◽  
Alfredo Goes ◽  
M. Fatima Leite
Keyword(s):  
Bioactive Glass ◽  
Calcium Channel ◽  
Intracellular Calcium ◽  
Subcellular Distribution ◽  
Glutamate Release ◽  
Calcium Entry ◽  
The Other ◽  
Inositol Triphosphate ◽  
Type I ◽  
Type Ii

Osteoblasts constitutively release glutamate and this release appears to be regulated by calcium entry. In this work we investigated if the bioactive glass with 60% of silicon (BG60S) could alter glutamate release by osteoblasts. We demonstrated that osteoblasts incubated with medium containing ionic products from the dissolution of BG60S showed lower release of glutamate when compared to control. Since intracellular calcium (Cai 2+) increase is required for glutamate release we investigated the subcellular distribution of the calcium channel inositol triphosphate receptors (InsP3Rs) in the presence of BG60S compared to control. We found that the type-III InsP3R was not expressed in osteoblast, while the type-II InsP3R was expressed mainly in the cytosol. We also found that the expression of type-II InsP3R decreased in BG60S treated osteoblasts compared to control. On the other hand, we found that the type-I InsP3R was expressed mainly in the nucleus and its expression increased in the presence of the biomaterial.

A continuum theory of disorder in nematic liquid crystals. - II. Intermolecular correlations

1977 ◽  
Vol 353 (1673) ◽  
pp. 261-275 ◽  
Keyword(s):  
Liquid Crystals ◽  
Order Parameter ◽  
Continuum Theory ◽  
The Other ◽  
Wave Number ◽  
Interesting Problem ◽  
Molecular Models ◽  
Partial Agreement ◽  
The Mean ◽  
The Continuum

The continuum theory of nematics suggested in paper I is used to derive an expression for the quantity < P 2 (cos γ ( R ))>, where γ is the angle between the director at two points separated by a distance R . The result tends to the Maier-Saupe limit (S 2 2 , corresponding to no correlations of orientation) for large R , but to unity for small R , while for the value of R corresponding to the mean intermolecular spacing it is about S α 0 2 , with α 0 close to unity. It is suggested that continuum theory may be used to estimate <sin γ ( R )> as well. Two simple molecular models for nematics are discussed in the light of these results, one of them a simplified version of the model on which Maier & Saupe originally based their theory, and the other a steric model of the sort proposed by Onsager. Predictions based upon these models concerning the Frank stiffness constants - in particular, concerning their dependence on the order parameter S 2 at constant volume and temperature and upon wave number q - are found to be in partial but only partial agreement with experiment. An interesting problem concerning the entropy of misalignment and its effect upon the stiffness of a nematic is left unresolved.

scholarly journals Yeast Bax Inhibitor (Bxi1p/Ybh3p) is a Calcium Channel in E. coli

2019 ◽  
Author(s):  
James Mullin ◽  
John Kalhorn ◽  
Nicholas Mello ◽  
Amanda Raffa ◽  
Alexander Strakosha ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Saccharomyces Cerevisiae ◽  
Calcium Channel ◽  
The Other ◽  
Bacterial Cells ◽  
E Coli ◽  
Founding Member ◽  
Bona Fide ◽  
Small Molecular Inhibitors

AbstractHuman Bax Inhibitor-1 (HsBI-1/TMBIM6) is the founding member of the evolutionary conserved TMBIM superfamily of proteins that share sequence homology within the transmembrane Bax inhibitor-containing motif (TMBIM). Mechanistically, BI-1/TMBIM6 and all the other mammalian TMBIM proteins appear to be involved in the maintenance of calcium homeostasis, and the crystal structure of a bacterial TMBIM protein, BsYetJ, suggests that the protein is a pH-sensitive calcium leak. The budding yeast, Saccharomyces cerevisiae, has a single TMBIM family member (YNL305C) named Bxi1p/Ybh3p. To determine the function of Bxi1p/Ybh3p, we overexpressed Bxi1p-EGFP in E. coli to determine if it is a calcium channel. We show that bacterial cells expressing Bxi1p-EGFP are more permeable to calcium than controls. Thus, our data suggests that yeast Bax inhibitor (Bxi1p) is a calcium channel in E. coli, lending support to our proposal that Bxi1p is a bona fide member of the TMBIM family of proteins. Further, we use our bacterial system to show that gadolinium is an inhibitor of Bxi1p in vivo, suggesting a path forward to identifying other small-molecular inhibitors of this clinically-important and highly conserved superfamily of proteins. Finally, parallel experiments revealed that the human Bax Inhibitor-1 (HsBI-1/TMBIM6) is also a calcium channel in bacteria that can be inhibited by gadolinium.

scholarly journals Molecular systematics of the subfamily Limenitidinae (Lepidoptera: Nymphalidae)

PeerJ ◽  
2018 ◽  
Vol 6 ◽  
pp. e4311 ◽  
Author(s):  
Bidur Dhungel ◽  
Niklas Wahlberg
Keyword(s):  
Molecular Systematics ◽  
Molecular Data ◽  
Molecular Methods ◽  
The Other ◽  
Data Matrix ◽  
Phylogenetic Hypothesis ◽  
Phylogenetic Studies

We studied the systematics of the subfamily Limenitidinae (Lepidoptera: Nymphalidae) using molecular methods to reconstruct a robust phylogenetic hypothesis. The molecular data matrix comprised 205 Limenitidinae species, four outgroups, and 11,327 aligned nucleotide sites using up to 18 genes per species of which seven genes (CycY, Exp1, Nex9, PolII, ProSup, PSb and UDPG6DH) have not previously been used in phylogenetic studies. We recovered the monophyly of the subfamily Limenitidinae and seven higher clades corresponding to four traditional tribes Parthenini, Adoliadini, Neptini, Limenitidini as well as three additional independent lineages. One contains the genera Harma + Cymothoe and likely a third, Bhagadatta, and the other two independent lineages lead to Pseudoneptis and to Pseudacraea. These independent lineages are circumscribed as new tribes. Parthenini was recovered as sister to rest of Limenitidinae, but the relationships of the remaining six lineages were ambiguous. A number of genera were found to be non-monophyletic, with Pantoporia, Euthalia, Athyma, and Parasarpa being polyphyletic, whereas Limenitis, Neptis, Bebearia, Euryphura, and Adelpha were paraphyletic.

scholarly journals Exploring Covalent Docking Mechanisms of Boron-Based Inhibitors to Class A, C and D β-Lactamases Using Time-dependent Hybrid QM/MM Simulations

2021 ◽  
Vol 8 ◽  
Author(s):  
Łukasz Charzewski ◽  
Krystiana A. Krzyśko ◽  
Bogdan Lesyng
Keyword(s):  
Molecular Modeling ◽  
Rational Design ◽  
Structural Changes ◽  
Molecular Design ◽  
Time Dependent ◽  
Molecular Medicine ◽  
Great Promise ◽  
Resistant Bacteria ◽  
Biological Targets ◽  
Covalent Docking

Recently, molecular covalent docking has been extensively developed to design new classes of inhibitors that form chemical bonds with their biological targets. This strategy for the design of such inhibitors, in particular boron-based inhibitors, holds great promise for the vast family of β-lactamases produced, inter alia, by Gram-negative antibiotic-resistant bacteria. However, the description of covalent docking processes requires a quantum-mechanical approach, and so far, only a few studies of this type have been presented. This study accurately describes the covalent docking process between two model inhibitors - representing two large families of inhibitors based on boronic-acid and bicyclic boronate scaffolds, and three β-lactamases which belong to the A, C, and D classes. Molecular fragments containing boron can be converted from a neutral, trigonal, planar state with sp2 hybridization to the anionic, tetrahedral sp3 state in a process sometimes referred to as morphing. This study applies multi-scale modeling methods, in particular, the hybrid QM/MM approach which has predictive power reaching well beyond conventional molecular modeling. Time-dependent QM/MM simulations indicated several structural changes and geometric preferences, ultimately leading to covalent docking processes. With current computing technologies, this approach is not computationally expensive, can be used in standard molecular modeling and molecular design works, and can effectively support experimental research which should allow for a detailed understanding of complex processes important to molecular medicine. In particular, it can support the rational design of covalent boron-based inhibitors for β-lactamases as well as for many other enzyme systems of clinical relevance, including SARS-CoV-2 proteins.

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