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in category pharmacology and toxicology

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21: The Environmental Risks of neonicotinoid pesticides: a review of the evidence post-2013
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Posted to bioRxiv 06 Jan 2017

The Environmental Risks of neonicotinoid pesticides: a review of the evidence post-2013
2,539 downloads pharmacology and toxicology

Thomas J. Wood, Dave Goulson

EXECUTIVE SUMMARY Neonicotinoid pesticides were first introduced in the mid-1990s and since then their use has grown rapidly so that they have become the most widely used class of insecticides in the world, with the majority being used as seed coatings. Neonicotinoids are water-soluble, and so a small quantity applied to a seed will dissolve when in contact with water in the soil and be taken up by the roots of the developing plant. Once inside the plant it becomes systemic and is found in vascular tissues and foliage, providing protection against herbivorous insects. This prophylactic use of neonicotinoids has become extremely widespread on a wide range of arable crops across much of the developed world. However, only approximately 5% of the neonicotinoid active ingredient is taken up by crop plants and most instead disperses into the wider environment. Since the mid-2000s numerous studies have raised concerns that neonicotinoids may be having a negative effect on non-target organisms. In particular, neonicotinoids were associated with mass poisoning events of honeybees and were shown to have serious negative effects on honeybee and bumblebee fitness when consumed. In response to this growing body of evidence, the European Food Safety Authority (EFSA) was commissioned to produce risk assessments for the use of clothianidin, imidacloprid and thiamethoxam and their impact on bees. These risk assessments, published in January 2013, conclude that the use of these compounds on certain flowering crops poses a high risk to bees. On the basis of these findings, the European Union adopted a partial ban on these substances in May 2013 which came into force on 1st December 2013. The purpose of this review is to collate and summarise scientific evidence published since 2013 that investigates the impact of neonicotinoids on non-target organisms and to bring it into one place to aid informed decision making. Due to international concern over the unintended impacts of neonicotinoids on wildlife, this topic has received a great deal of scientific attention in this three year period. As the restrictions were put in place because of the risk neonicotinoids pose to bees, much of the recent research work has naturally focussed on this group. Risks to bees Broadly, the EFSA risk assessments addressed risks of exposure to bees from neonicotinoids through various routes and the direct lethal and sublethal impact of neonicotinoid exposure. New scientific evidence is available in all of these areas, and it is possible to comment on the change in the scientific evidence since 2013 compared to the EFSA reports. This process is not meant to be a formal assessment of the risk posed by neonicotinoids in the manner of that conducted by EFSA. Instead it aims to summarise how the new evidence has changed our understanding of the likely risks to bees; is it lower, similar or greater than the risk perceived in 2013. With reference to the EFSA 2013 risk assessments baseline, advances in each considered area and their impact on the original assessment can be summarised thus: * Risk of exposure from pollen and nectar of treated flowering crops. The EFSA reports calculated typical exposure from flowering crops treated with neonicotinoids as seed dressings. Considerably more data are now available in this area, with new studies broadly supporting the calculated exposure values. For bees, flowering crops pose a Risk Unchanged to that reported by EFSA 2013. * Risk from non-flowering crops and cropping stages prior to flowering. Non-flowering crops were considered to pose no risk to bees. No new studies have demonstrated that these non-flowering crops pose a direct risk to bees. They remain a Risk Unchanged. * Risk of exposure from the drilling of treated seed and subsequent dust drift. Despite modification in seed drilling technology, available studies suggest that dust drift continues to occur, and that dust drift still represents a source of acute exposure and so is best considered a Risk Unchanged. * Risk of exposure from guttation fluid. Based on available evidence this was considered a low-risk exposure path by EFSA 2013. New data have not changed this position and so it remains a Risk Unchanged. * Risk of exposure from and uptake of neonicotinoids in non-crop plants. Uptake of neonicotinoids by non-target plants was considered likely to be negligible, though a data gap was identified. Many studies have since been published demonstrating extensive uptake of neonicotinoids and their presence in the pollen, nectar and foliage of wild plants. Bees collecting pollen from neonicotinoid-treated crops can generally be expected to be exposed to the highest neonicotinoid concentrations, but non-trivial quantities of neonicotinoids are also present in pollen and nectar collected from wild plants, and this source of exposure may be much more prolonged than the flowering period of the crop. Exposure from non-target plants clearly represents a Greater Risk. * Risk of exposure from succeeding crops. A data gap was identified for this issue. Few studies have explicitly investigated this, but this area does represent some level of risk as neonicotinoids are now known to have the potential to persist for years in soil, and can be detected in crops multiple years after the last known application. However, as few data exist this is currently considered a Risk Unchanged. * Direct lethality of neonicotinoids to adult bees. Additional studies on toxicity to honeybees have supported the values calculated by EFSA. More data have been produced on neonicotinoid toxicity for wild bee species and meta-analyses suggest a broadly similar response. Reference to individual species is important but neonicotinoid lethality should be broadly considered a Risk Unchanged. * Sublethal effects of neonicotinoids on wild bees. Consideration of sublethal effects by EFSA was limited as there is no agreed testing methodology for the assessment of such effects. A data gap was identified. Exposure to neonicotinoid-treated flowering crops has been shown to have significant negative effects on free flying wild bees under field conditions and some laboratory studies continue to demonstrate negative effects on bee foraging ability and fitness using field-realistic neonicotinoid concentrations. Greater Risk. Within this context, research produced since 2013 suggest that neonicotinoids pose a similar to greater risk to wild and managed bees, compared to the state of play in 2013. Given that the initial 2013 risk assessment was sufficient to impose a partial ban on the use of neonicotinoids on flowering crops, and given that new evidence either confirms or enhances evidence of risk to bees, it is logical to conclude that the current scientific evidence supports the extension of the moratorium, and that the extension of the partial ban to other uses of neonicotinoids should be considered. Broader risks to environmental health In addition to work on bees, our scientific understanding has also been improved in the following areas which were not previously considered by EFSA: * Non-flowering crops treated with neonicotinoids can pose a risk to non-target organisms through increasing mortality in beneficial predator populations. * Neonicotinoids can persist in agricultural soils for several years, leading to chronic contamination and, in some instances, accumulation over time. * Neonicotinoids continue to be found in a wide range of different waterways including ditches, puddles, ponds, mountain streams, rivers, temporary wetlands, snowmelt, groundwater and in outflow from water processing plants. * Reviews of the sensitivity of aquatic organisms to neonicotinoids show that many aquatic insect species are several orders of magnitude more sensitive to these compounds than the traditional model organisms used in regulatory assessments for pesticide use. * Neonicotinoids have been shown to be present in the pollen, nectar and foliage of non-crop plants adjacent to agricultural fields. This ranges from herbaceous annual weeds to perennial woody vegetation. We would thus expect non-target herbivorous insects and non-bee pollinators inhabiting field margins and hedgerows to be exposed to neonicotinoids. Of particular concern, this includes some plants sown adjacent to agricultural fields specifically for the purposes of pollinator conservation. * Correlational studies have suggested a negative link between neonicotinoid usage in agricultural areas and population metrics for butterflies, bees and insectivorous birds in three different countries. Overall, this recent work on neonicotinoids continues to improve our understanding of how these compounds move through and persist in the wider environment. These water soluble compounds are not restricted to agricultural crops, instead permeating most parts of the agricultural environments in which they are used and in some cases reaching further afield via waterways and runoff water. Field-realistic laboratory experiments and field trials continue to demonstrate that traces of residual neonicotinoids can have a mixture of lethal and sublethal effects on a wide range of taxa. Susceptibility varies tremendously between different taxa across many orders of magnitude, with some showing a negative response at parts per billion with others show no such effects at many thousands of parts per billion. Relative to the risk assessments produced in 2013 for clothianidin, imidacloprid and thiamethoxam which focussed on their effects on bees, new research strengthens arguments for the imposition of a moratorium, in particular because it has become evident that they pose significant risks to many non-target organisms, not just bees. Given the improvement in scientific knowledge of how neonicotinoids move into the wider environment from all crop types, a discussion of the risks posed by their use on non-flowering crops and in non-agricultural areas is urgently needed.

22: A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study
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Posted to bioRxiv 10 Jul 2020

A Strategy to Treat COVID-19 Disease with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study
2,502 downloads pharmacology and toxicology

Tien-Tzu Tai, Tzung-Ju Wu, Huey-Dong Wu, Yi-Chen Tsai, Hui-Ting Wang, An-Min Wang, Sheue-Fang Shih, Yee-Chun Chen

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing coronavirus disease 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection in vitro and tested in clinical studies. However, lung concentration (6.7 μg/mL) to predict the in vivo antiviral efficacy might not be achievable with the currently proposed oral dosing regimen. Further, a high cumulative doses of HCQ may raise concerns of systemic toxicity, including cardiotoxicity. Here, we described a non-clinical study to investigate the pharmacokinetics of a novel formulation of liposomal HCQ administrated by intratracheal (IT) instillation in Sprague-Dawley (SD) rats which achieved 129.4 μg/g (Cmax) in the lung. Compared to unformulated HCQ administered intravenous (IV), liposomal HCQ with normalized dose showed higher (~30-fold) lung exposure, longer (~2.5-fold) half-life in lung, but lower blood exposure with ~20% of Cmax and 74% of AUC and lower heart exposure with 24% of Cmax and 58% of AUC. In conclusion, the pharmacokinetics results in an animal model demonstrate the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.

23: Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region
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Posted to bioRxiv 11 Jun 2020

Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region
2,478 downloads pharmacology and toxicology

Adriana Carino, Federica Moraca, Bianca Fiorillo, Silvia Marchianò, Valentina Sepe, Michele Biagioli, Claudia Finamore, Silvia Bozza, Daniela Francisci, Eleonora Distrutti, Bruno Catalanotti, Angela Zampella, Stefano Fiorucci

The coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus (SARS)-CoV-2. In the light of the urgent need to identify novel approaches to be used in the emergency phase, a largely explored strategy has been the repurpose of clinically available drugs as new antivirals, by targeting different viral proteins. In this paper, we describe a drug repurposing strategy based on a virtual screening of druggable pockets located in the central β-sheet core of the SARS-CoV-2 Spike protein RBD supported by in vitro tests identifying several steroidal derivatives as SARS-CoV-2 entry inhibitors. Our results demonstrate that several potential binding sites exist in the SARS CoV-2 S protein, and that the occupancy of these pockets reduces the ability of the S protein RBD to bind to the ACE2 consensus in vitro. In particular, natural occurring and clinically available steroids as glycyrrhetinic and oleanolic acids, as well as the bile acids derivatives glyco-UDCA and obeticholic acid have been shown to be effective in preventing virus entry in the case of low viral load. All together, these results might help to define novel approaches to reduce the viral load by using SARS-CoV-2 entry inhibitors. ### Competing Interest Statement This paper was supported by a research grant by BAR Pharmaceuticals S.r.L. to the Department of Pharmacy of the University of Napoli Federico II and to the Department of Surgical and Biomedical Sciences, University of Perugia. The authors declare the following competing financial interest(s): S.F., A.Z. and B.C. have filed an Italian patent application no.102020000011092 in the name of BAR Pharmaceuticals S.r.L. on the compounds described in this paper.

24: Best Practices in Docking and Activity Prediction
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Posted to bioRxiv 12 Feb 2016

Best Practices in Docking and Activity Prediction
2,471 downloads pharmacology and toxicology

Manuel Rueda, Ruben Abagyan

During the last decade we witnessed how computational docking methods became a crucial tool in the search for new drug candidates. The 'central dogma' of small molecule docking is that compounds that dock correctly into the receptor are more likely to display biological activity than those that do not dock. This 'dogma', however, possesses multiple twists and turns that may not be obvious to novice dockers. The first premise is that the compounds must dock; this implies: (i) availability of data, (ii) realistic representation of the chemical entities in a form that can be understood by the computer and the software, and, (iii) exhaustive sampling of the protein-ligand conformational space. The second premise is that, after the sampling, all docking solutions must be ranked correctly with a score representing the physico-chemical foundations of binding. The third premise is that 'correctness' must be defined unambiguously, usually by comparison with 'static' experimental data (or lack thereof). Each of these premises involves some degree of simplification of reality, and overall loss in the accuracy of the docking predictions. In this chapter we will revise our latest experiences in receptor-based docking when dealing with all three above-mentioned issues. First, we will explain the theoretical foundation of ICM docking, along with a brief explanation on how we measure performance. Second, we will contextualize ICM by showing its performance in single and multiple receptor conformation schemes with the Directory of Useful Decoys (DUD) and the Pocketome. Third, we will describe which strategies we are using to represent protein plasticity, like using multiple crystallographic structures or Monte Carlo (MC) and Normal Mode Analysis (NMA) sampling methods, emphasizing how to overcome the associated pitfalls (e.g., increased number of false positives). In the last section, we will describe ALiBERO, a new tool that is helping us to improve the discriminative power of X-ray structures and homology models in screening campaigns.

25: Repurposed High-Throughput Images Enable Biological Activity Prediction For Drug Discovery
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Posted to bioRxiv 29 Mar 2017

Repurposed High-Throughput Images Enable Biological Activity Prediction For Drug Discovery
2,357 downloads pharmacology and toxicology

Jaak Simm, Günter Klambauer, Adam Arany, Marvin Steijaert, Jörg Kurt Wegner, Emmanuel Gustin, Vladimir Chupakhin, Yolanda T. Chong, Jorge Vialard, Peter Buijnsters, Ingrid Velter, Alexander Vapirev, Shantanu Singh, Anne Carpenter, Roel Wuyts, Sepp Hochreiter, Yves Moreau, Hugo Ceulemans

We repurpose a High-Throughput (cell) Imaging (HTI) screen of a glucocorticoid receptor assay to predict target protein activity in multiple other seemingly unrelated assays. In two ongoing drug discovery projects, our repurposing approach increased hit rates by 60- to 250-fold over that of the primary project assays while increasing the chemical structure diversity of the hits. Our results suggest that data from available HTI screens are a rich source of information that can be reused to empower drug discovery efforts.

26: Silver fluoride as a treatment for the disease dental caries
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Posted to bioRxiv 20 Jun 2017

Silver fluoride as a treatment for the disease dental caries
2,160 downloads pharmacology and toxicology

Jeremy A Horst, Jong Seto

The current paradigm of treatment for dental caries (tooth decay) in primary teeth is dangerous, fails to reach many children, and suffers high recurrence. Acceptance of the paradigm arises from a misperception that untreated caries in primary teeth is a threat to life. We show a linear relationship between age and deaths in the United States from 1999 through 2015 caused by dental caries, pulpal/periapical abscess, or facial cellulitis. The intercept of 6 years coincides with emergence of the first permanent tooth: it appears that caries in primary teeth is not a threat to life. Thus, treatment goals should be to avoid pain, which is not possible with operative dentistry, as it causes pain. Medical management of caries is a distinct treatment philosophy which employs topical minimally invasive therapies that treat the disease, and is not merely prevention. Silver diamine fluoride (SDF) is a central agent to enable effective non-invasive treatment. The announcement of FDA Breakthrough Therapy designation suggests that SDF will become the first FDA approved drug for treating the disease dental caries. Since our last review, 4 clinical trials have been completed, which inform an update to the application protocol and frequency regimen. Suggestions from these studies are to skip the rinsing step due to demonstration of safety and concern of diminished effectiveness by dilution, and to start patients with an intensive regimen of multiple applications over the first few weeks. Breakthroughs in elucidating the impact of SDF on tooth structure and the plaque microbiome inform potential opportunities for bioengineering and understanding caries arrest, respectively. Dentists have been surprised by preference of this treatment over traditional invasive approaches. Renewed interest in this old material has delivered progress to optimize the judicious use of SDF, and enable a revolution in caries management, particularly for primary teeth.

27: Hematological and Serum Biochemical Analysis of Streptozotocin-Induced Insulin Dependent Diabetes Mellitus in Male Adult Wistar Rats
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Posted to bioRxiv 30 Jun 2018

Hematological and Serum Biochemical Analysis of Streptozotocin-Induced Insulin Dependent Diabetes Mellitus in Male Adult Wistar Rats
2,093 downloads pharmacology and toxicology

Nima Yakhchalian, Nasim mohammadian, Kazem Hatami, Hamed Nosrati, Namdar Yousofvand

Background: This investigation is concentrated on how hematological and serum biochemical markers would change in streptozotocin-induced Insulin-Dependent diabetes mellitus(IDDM) in male adult wistar rats. Hematological parameters, serum protein electrophoresis parameters and hepatic transaminases level (SGOT-SGPT) were all measured in both control group rats (N=6) and diabetic group rats (N=6) and comparison between two groups was performed. Material and Method: Single dose intraperitoneal injection of 60 mg/kg dose of streptozotocin(STZ) in male adult wistar rats, induces extensive necrosis in langerhans β-cell islets, because of its cytotoxicity. Experimental diabetes mellitus can be induced completely in less than 72 hours after STZ intraperitoneal injection. Streptozotocin(STZ) was purchased from Sigma company. Diabetic and control group rats were kept separately in different metabolic cages, and their blood glucose(BG), hematological parameters, serum protein electrophoretic pattern and hepatic transaminases level were analyzed and comparison was done. Results: In our investigation, Insulin-Dependent Diabetes Mellitus (IDDM) was completely induced one week after single intraperitoneal injection of 60 mg/kg BW. Diabetes mellitus induction was verified by measuring fasting plasma glucose level in blood samples of rats. Level of blood glucose, hematological parameters, serum protein electrophoretic pattern and hepatic transaminase enzymes level, were all measured. In diabetic group rats level of blood glucose (BG), hepatic transaminase enzymes (SGOT & SGPT), serum α1-globulin and β-globulin were significantly increased but in albumin, albumin/globulin ratio (A/G ratio) and serum α2-globulin a significant decrease was observed in diabetic rats in comparison with normal rats. Conclusion: Extensive inflammation and tissue necrosis induced following diabetes mellitus induction in rats. Significant alterations were observed in serum protein electrophoresis fractions and hepatic transaminase enzymes level due to streptozotocin cytotoxic impacts on some tissues specifically liver. Because of extensive β-cells necrosis and degeneration caused by streptozotocin exposure, high level of blood glucose (diabetic hyperglycemia) was observed in diabetic rats. This type of experimentally induced diabetes mellitus would highly affect hematological parameters. Insulin-Dependent Diabetes Mellitus induced by streptozotocin, can lead to anemia, neutrophilia and lymphocytosis and also has decreasing effects on red blood cell indices (HGB, MCV, MCH, MCHC) in diabetic group rats. Keywords: Serum Protein Electrophoresis, Hematology, Diabetes Mellitus, Streptozotocin, Transaminase, STZ-Induced Diabetes Mellitus

28: Differential GLP-1R binding and activation by peptide and non-peptide agonists
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Posted to bioRxiv 16 Aug 2020

Differential GLP-1R binding and activation by peptide and non-peptide agonists
1,989 downloads pharmacology and toxicology

Xin Zhang, Matthew Belousoff, Peishen Zhao, Albert J. Kooistra, Tin T Truong, Sheng Yu Ang, Christina Rye Underwood, Thomas Egebjerg, Petr Senel, Gregory D Stewart, Yi-Lynn Liang, Alisa Glukhova, Hari Venugopal, Arthur Christopoulos, Sebastian GB Furness, Laurence J Miller, Steffen Reedtz-Runge, Christopher J. Langmead, David E. Gloriam, Radostin Danev, Patrick M. Sexton, Denise Wootten

Peptide drugs targeting class B1 GPCRs can treat multiple diseases, however there remains substantial interest in the development of orally delivered non-peptide drugs. Here we reveal unexpected overlap between signalling and regulation of the glucagon-like peptide-1 (GLP-1) receptor by the non-peptide agonist, PF 06882961, and GLP-1 that was not observed for another compound, OWL-833. Both compounds are currently in clinical trials for treatment of type 2 diabetes. High resolution cryo-EM structures reveal the binding sites for PF-06882961 and GLP-1 substantially overlap, whereas OWL-833 adopts a unique binding mode with a more open receptor conformation at the extracellular face. Structural differences involving extensive water-mediated hydrogen bond networks could be correlated to functional data to understand how PF 06882961, but not OWL-833, can closely mimic the pharmacological properties of GLP-1. These findings will facilitate rational structure-based discovery of non-peptide agonists targeting class B GPCRs. ### Competing Interest Statement C.R.U, T.E and S.R-R are employees of Novo Nordisk. P.S is an employee of Apigenex.

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Posted to bioRxiv 21 Mar 2016

1,948 downloads pharmacology and toxicology

Maria Angelica M Duque, Rhowell N Tiozon, Rebecca C. Nueva España

Nanotechnology and its promises for clinical translation to targeted drug delivery with limited accompanying toxicity provide exciting research opportunities that demands multidisciplinary approaches. The colloidal metallic systems have been recently investigated in the area of nanomedicine. Gold nanoparticles have found themselves useful for diagnostics and drug delivery applications. In this study, we have reported a novel method for the synthesis of gold nanoparticles using natural, biocompatible and biodegradable chitosan which came from deacetylating chitin from Portunus Pelagicus. It serves many purposes, as a reducing agent, stabilizer and absorption and penetration enhancer. Erythropoietin would have high loading efficiency with chitosan reduced gold nanoparticles; the binding is predominantly through hydrogen bonding. Chitosan reduced gold nanoparticles improve the pharmacodynamics and cellular uptake of Erythropoietin across mucosal sites and have immunoadjuvant properties. There is almost 50 % shell waste in crustacean industry. It is resourceful if it would be bioconverted. The process of bioconversion is deproteination, demineralization and deacetylation to obtain chitosan. In synthesizing gold nanoparticles, 1.48 x 10-2 M chloroauric acid will be reduced by heating for 15 minutes in 100mL chitosan solution prepared in 1% acetic acid to yield a ruby-red solution. Erythropoietin would be loaded into it and will undergo 13,000rpm of centrifuge followed by calculating the loading efficiency.

30: Virtual screening of inhibitors for the Zika virus proteins
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Posted to bioRxiv 28 Jun 2016

Virtual screening of inhibitors for the Zika virus proteins
1,944 downloads pharmacology and toxicology

S. Feranchuk, U. Potapova, S. Belikov

The NS3 protease and NS5 polymerase structures of the Zika virus were constructed and processed using a virtual screening pipeline. MM-PBSA calculations show that some of the ligands found by the pipeline demonstrate a good affinity to vulnerable sites in both proteins. The anti-hypertension drug eprosartan is among the selected ligands; and inhibition of the tick-borne encephalitis virus has already been confirmed in vivo by a previous study. In the present study phytochemicals bisabolol and andrographolide are suggested as the candidates for antiviral therapy.

31: Approaches for calculating solvation free energies and enthalpies demonstrated with an update of the FreeSolv database
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Posted to bioRxiv 30 Jan 2017

Approaches for calculating solvation free energies and enthalpies demonstrated with an update of the FreeSolv database
1,937 downloads pharmacology and toxicology

Guilherme Duarte Ramos Matos, Daisy Y. Kyu, Hannes H. Loeffler, John D Chodera, Michael R. Shirts, David L. Mobley

Solvation free energies can now be calculated precisely from molecular simulations, providing a valuable test of the energy functions underlying these simulations. Here, we briefly review "alchemical" approaches for calculating the solvation free energies of small, neutral organic molecules from molecular simulations, and illustrate by applying them to calculate aqueous solvation free energies (hydration free energies). These approaches use a non-physical pathway to compute free energy differences from a simulation or set of simulations and appear to be a particularly robust and general-purpose approach for this task. We also present an update (version 0.5) to our FreeSolv database of experimental and calculated hydration free energies of neutral compounds and provide input files in formats for several simulation packages. This revision to FreeSolv provides calculated values generated with a single protocol and software version, rather than the heterogeneous protocols used in the prior version of the database. We also further update the database to provide calculated enthalpies and entropies of hydration and some experimental enthalpies and entropies, as well as electrostatic and nonpolar components of solvation free energies.

32: Targeting the Administration of Ecdysterone in Doping Control Samples
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Posted to bioRxiv 27 Jun 2019

Targeting the Administration of Ecdysterone in Doping Control Samples
1,862 downloads pharmacology and toxicology

Maria Kristina Parr, Gabriella Ambrosio, Bernhard Wuest, Monica Mazzarino, Xavier de la Torre, Francesca Sibilia, Jan Felix Joseph, Patrick Diel, Francesco Botrè

Purpose: The phytosteroid ecdysterone was recently reported to enhance performance in sports and may thus be considered as a substance of relevance in anti-doping control. To trace back an administration of ecdysterone from urine samples analytical properties have been investigated to assess its integration into initial testing procedures (ITP) in doping control laboratories. Methods: Analytical properties of ecdysterone were evaluated using GC-QTOF-MS and LC-QTOF-MS. Its metabolism and elimination in human were studied using urines collected after administration. Results: The detectability of ecdysterone by GC-MS (after derivatization) and/or LC-MS(/MS) has been demonstrated and sample preparation methods were evaluated. Dilute-and-inject for LC-MS(/MS) or SPE using Oasis HLB for GC-MS or LC-MS were found most suitable, while liquid-liquid extraction was hampered by the high polarity of ecdysteroids. Most abundantly, ecdysterone was detected in the post administration urines as parent compound besides the metabolite desoxy-ecdysterone. Additionally desoxy-poststerone was tentatively assigned as minor metabolite, however further investigations are needed. Conclusion: An administration of ecdysterone can be targeted using existing procedures of anti-doping laboratories. Ecdysterone and desoxy-ecdysterone appeared as suitable candidates for integration in ITP. Using dilute-and-inject a detection of the parent compound was possible for more than two days after the administration of a single dose of ~50 mg.

33: Immunoglobulin fragment F(ab')2 against RBD potently neutralizes SARS-CoV-2 in vitro
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Posted to bioRxiv 09 Apr 2020

Immunoglobulin fragment F(ab')2 against RBD potently neutralizes SARS-CoV-2 in vitro
1,842 downloads pharmacology and toxicology

Xiaoyan Pan, Pengfei Zhou, Tiejiong Fan, Yan Wu, Jing Zhang, Xiaoyue Shi, Weijuan Shang, Lijuan Fang, Xiaming Jiang, Jian Shi, Yuan Sun, Shaojuan Zhao, Rui Gong, Ze Chen, Gengfu Xiao

COVID-19 caused by the emerging human coronavirus, SARS-CoV-2, has become a global pandemic, leading a serious threat to human health. So far, there is none vaccines or specific antiviral drugs approved for that. Therapeutic antibodies for SARS-CoV-2, was obtained from hyper immune equine plasma in this study. Herein, SARS-CoV-2 RBD with gram level were obtained through Chinese hamster ovary cells high-density fermentation. The binding of RBD to SARS-CoV-2 receptor, human ACE2, was verified and the efficacy of RBD in vivo was tested on mice and then on horses. As a result, RBD triggered high-titer neutralizing antibodies in vivo, and immunoglobulin fragment F(ab')2 was prepared from horse antisera through removing Fc. Neutralization test demonstrated that RBD-specific F(ab')2 inhibited SARS-CoV-2 with EC50 at 0.07 μg/ml, showing a potent inhibitory effect on SARS-CoV-2. These results highlights as RBD-specific F(ab')2 as therapeutic candidate for SARS-CoV-2. ### Competing Interest Statement

34: The off-target kinase landscape of clinical PARP inhibitors
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Posted to bioRxiv 14 Jan 2019

The off-target kinase landscape of clinical PARP inhibitors
1,833 downloads pharmacology and toxicology

Albert A. Antolin, Malaka Ameratunga, Udai Banerji, Paul A. Clarke, Paul Workman, Bissan Al-Lazikani

Four PARP inhibitors have been approved by the FDA as cancer therapeutics, yet there are several clinical settings where no strong rationale exists to inform clinicians on which to choose in terms of clinical effectiveness and toxicity. The four drugs have largely similar PARP family inhibition profiles, but several differences at the molecular and clinical level have been reported that remain poorly understood. We previously hypothesized that PARP inhibitors could have an inherent capacity to inhibit kinases off-target. Here, we characterise the off-target kinase landscape of four FDA-approved PARP drugs. We demonstrate that all four PARP inhibitors have a unique polypharmacological profile across the kinome. Niraparib and rucaparib inhibit DYRK1s, CDK16 and PIM3 at clinically achievable submicromolar concentrations. These represent the most potently inhibited off-targets of PARP inhibitors identified to date and should be investigated further to clarify their potential implications for efficacy and safety in the clinic, including use of PARP inhibitors in combination with other agents, including immunotherapy.

35: Mid-Infrared Spectroscopy Study of Effects of Neonicotinoids on Forager Honey Bee (Apis mellifera) Fat Bodies and Their Connection to Colony Collapse Disorder
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Posted to bioRxiv 18 Oct 2017

Mid-Infrared Spectroscopy Study of Effects of Neonicotinoids on Forager Honey Bee (Apis mellifera) Fat Bodies and Their Connection to Colony Collapse Disorder
1,828 downloads pharmacology and toxicology

Yuzheng Feng, Aryan Luthra, Kaiwen Ding, Yang Yang, Jordan Savage, Xinrui Wei, Roland Moeschter, Sachin Ahuja, Victor Villegas, Bogdana Torbina, Anjuli Ahooja, Tom Ellis, Anna-Maria Boechler, Andrew Roberts

This study investigated the negative effects of neonicotinoid pesticides on honey bees in environment surrounding areas of pesticide use. The aim of the experiment is to identify possible contributors to the sudden decrease in honey bee population over the past 60 years, a phenomenon known as Colony Collapse Disorder. Analysis was performed on three sets of bees: the control group which was not in contact with pesticides, the infected dead group which was a set of bees suspected to have died due to neonicotinoids, and the infected alive group which was suspected to be under the influence of neonicotinoids. After dissecting the bee samples and extracting their fat bodies, the chemical composition and protein structures of the samples were analyzed using Mid-Infrared Beamline at the Canadian Light Source. Results from the spectra of bee samples exposed to neonicotinoids demonstrated possible residual pesticide chemicals within fat bodies. Several spectral peaks were also correlated with a possible change in protein secondary structures from primarily β-sheet to α-helix within fat bodies of neonicotinoid-affected bees. It is likely that the pesticides caused the growth of additional α-helical structures, which is consistent with consequences of the inhibition of nicotinic acetylcholine receptors (nAChRs), which is a pathway of harm of Colony Collapse Disorder as identified in past literature.

36: The SARS-CoV-2 cytopathic effect is blocked with autophagy modulators
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Posted to bioRxiv 21 May 2020

The SARS-CoV-2 cytopathic effect is blocked with autophagy modulators
1,819 downloads pharmacology and toxicology

Kirill Gorshkov, Catherine Z Chen, Robert Bostwick, Lynn Rasmussen, Miao Xu, Manisha Pradhan, Bruce Nguyen Tran, Wei Zhu, Khalida Shamim, Wenwei Huang, Xin Hu, Min Shen, Carleen Klumpp-Thomas, Zina Itkin, Paul Shinn, Anton Simeonov, Sam Michael, Matthew D. Hall, Donald C. Lo, Wei Zheng

SARS-CoV-2 is a new type of coronavirus capable of rapid transmission and causing severe clinical symptoms; much of which has unknown biological etiology. It has prompted researchers to rapidly mobilize their efforts towards identifying and developing anti-viral therapeutics and vaccines. Discovering and understanding the virus' pathways of infection, host-protein interactions, and cytopathic effects will greatly aid in the design of new therapeutics to treat COVID-19. While it is known that chloroquine and hydroxychloroquine, extensively explored as clinical agents for COVID-19, have multiple cellular effects including inhibiting autophagy, there are also dose-limiting toxicities in patients that make clearly establishing their potential mechanisms-of-action problematic. Therefore, we evaluated a range of other autophagy modulators to identify an alternative autophagy-based drug repurposing opportunity. In this work, we found that 6 of these compounds blocked the cytopathic effect of SARS-CoV-2 in Vero-E6 cells with EC50 values ranging from 2.0 to 13 μM and selectivity indices ranging from 1.5 to >10-fold. Immunofluorescence staining for LC3B and LysoTracker dye staining assays in several cell lines indicated their potency and efficacy for inhibiting autophagy correlated with the measurements in the SARS-CoV-2 cytopathic effect assay. Our data suggest that autophagy pathways could be targeted to combat SARS-CoV-2 infections and become an important component of drug combination therapies to improve the treatment outcomes for COVID-19. ### Competing Interest Statement The authors have declared no competing interest.

37: Absence of entourage: Terpenoids commonly found in Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1 and CB2 receptors
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Posted to bioRxiv 06 Mar 2019

Absence of entourage: Terpenoids commonly found in Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1 and CB2 receptors
1,795 downloads pharmacology and toxicology

Marina Santiago, Shivani Sachdev, Jonathon C Arnold, Iain S McGregor, Mark Connor

Introduction: Compounds present in Cannabis sativa such as phytocannabinoids and terpenoids, may act in concert to elicit therapeutic effects. Cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) directly activate cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), however, it is not known if terpenoids present in Cannabis also affect cannabinoid receptor signalling. Therefore, we examined 6 common terpenoids alone, and in combination with cannabinoid receptor agonists, on CB1 and CB2 signalling in vitro. Materials and Methods: Potassium channel activity in AtT20 FlpIn cells transfected with human CB1 or CB2 receptors was measured in real-time using FLIPR membrane potential dye in a FlexStation 3 plate reader. Terpenoids were tested individually and in combination for periods up to 30 minutes. Endogenous somatostatin receptors served as a control for direct effects of drugs on potassium channels. Results: α-Pinene, β-pinene, β-caryophyllene, linalool, limonene and β-myrcene (up to 30-100 μM) did not change membrane potential in AtT20 cells expressing CB1 or CB2, or affect the response to a maximally effective concentration of the synthetic cannabinoid CP55,940. The presence of individual or a combination of terpenoids did not affect the hyperpolarization produced by Δ9-THC (10μM): (CB1: control, 59 ± 7%; with terpenoids (10 μM each) 55 ± 4%; CB2: Δ9-THC 16±5%, with terpenoids (10 μM each) 17±4%). To investigate possible effect on desensitization of CB1 responses, all six terpenoids were added together with Δ9-THC and signalling measured continuously over 30 min. Terpenoids did not affect desensitization, after 30 minutes the control hyperpolarization recovered by 63±6%, in the presence of the terpenoids recovery was 61±5%. Discussion: None of the six of the most common terpenoids in Cannabis directly activated CB1 or CB2, or modulated the signalling of the phytocannabinoid agonist Δ9-THC. These results suggest that if a phytocannabinoid-terpenoid entourage effect exists, it is not at the CB1 or CB2 receptor level. It remains possible that terpenoids activate CB1 and CB2 signalling pathways that do not involve potassium channels, however, it seems more likely that they may act at different molecular target(s) in the neuronal circuits important for the behavioural effect of Cannabis.

38: Curcumin Analogues as the Inhibitors of TLR4 Pathway in Inflammation and Their Drug Like Potentialities: A Computer-based Study
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Posted to bioRxiv 28 Jan 2020

Curcumin Analogues as the Inhibitors of TLR4 Pathway in Inflammation and Their Drug Like Potentialities: A Computer-based Study
1,794 downloads pharmacology and toxicology

Md. Asad Ullah, Fatema Tuz Johora, Bishajit Sarkar, Yusha Araf, MD. Hasanur Rahman

In this study Curcumin and their different analogues have been analyzed as the inhibitors of signaling proteins i.e., Cycloxygenase-2 (COX-2), Inhibitor of Kappaβ Kinase (IKK) and TANK binding kinase-1 (TBK-1) of Toll Like Receptor 4 (TLR4) pathway involved in inflammation using computational tools. Multiple analogues showed better binding affinity than the approved drugs for the respective targets. Upon continuous computational exploration 6-Gingerol, Yakuchinone A and Yakuchinone B were identified as the best inhibitors of COX-2, IKK and TBK-1 respectively. Then their drug like potentialities were analyzed in different experiments where they also performed sound and similar. Hopefully, this study will uphold the efforts of researchers to identify anti-inflammatory drugs from natural sources.

39: Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways
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Posted to bioRxiv 23 Mar 2018

Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways
1,790 downloads pharmacology and toxicology

Maire F. Osborn, Andrew H Coles, Annabelle Biscans, Reka A Haraszti, Loic Roux, Sarah Davis, Socheata Ly, Dimas Echeverria, Matthew R Hassler, Bruno M.D.C. Godinho, Mehran Nikan, Anastasia Khvorova

Efficient delivery of therapeutic RNA is the fundamental obstacle preventing its clinical utility. Lipid conjugation improves plasma half-life, tissue accumulation, and cellular uptake of small interfering RNAs (siRNAs). However, the impact of conjugate structure and hydrophobicity on siRNA pharmacokinetics is unclear, impeding the design of clinically relevant lipid-siRNAs. Using a panel of biologically-occurring lipids, we show that lipid conjugation modulates siRNA hydrophobicity and governs spontaneous partitioning into distinct plasma lipoprotein classes in vivo. Lipoprotein binding influences siRNA distribution by delaying renal excretion and promoting uptake into lipoprotein receptor-enriched tissues. Lipid-siRNAs elicit mRNA silencing without causing toxicity in a tissue-specific manner. Lipid-siRNA internalization occurs independently of lipoprotein endocytosis, and is mediated by siRNA phosphorothioate modifications. Although biomimetic lipoprotein nanoparticles have been considered for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation.

40: MDMA impairs response to water intake in healthy volunteers
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Posted to bioRxiv 18 Jun 2015

MDMA impairs response to water intake in healthy volunteers
1,788 downloads pharmacology and toxicology

Matthew J. Baggott, Kathleen J Garrison

Hyponatremia is a serious complication of 3,4-methylenedioxymethamphetamine (MDMA) use. We investigated potential mechanisms in two double-blind, placebo-controlled studies. In study 1, healthy drug-experienced volunteers received MDMA or placebo alone and in combination with the alpha-1 adrenergic inverse agonist prazosin, used as a positive control to release antidiuretic hormone (ADH). In study 2, volunteers received MDMA or placebo followed by standardized water intake. MDMA lowered serum sodium, but did not increase ADH or copeptin, although the control prazosin did increase ADH. Water loading reduced serum sodium more after MDMA than after placebo. There was a trend for women to have lower baseline serum sodium than men, but there were no significant interactions with drug condition. Combining studies, MDMA potentiated the ability of water to lower serum sodium. Thus, hyponatremia appears to be a significant risk when hypotonic fluids are consumed during MDMA use. Clinical trials and events where MDMA use is common should anticipate and mitigate this risk.

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