Several New Diverse Anticonvulsant Agents Discovered in a Virtual Screening Campaign Aimed at Novel Antiepileptic Drugs to Treat Refractory Epilepsy

Ianni, Mauricio E. Di; Enrique, Andrea; Palestro, Pablo Hernán; Gavernet, Luciana; Talevi, Alan; Bruno-Blanch, Luis E.

doi:10.1021/ci300423q

Cited by 13 publications

(9 citation statements)

References 39 publications

(57 reference statements)

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“…Animal models in biomedical research are important to improve in vivo understanding of the physiology of living organisms as well as the pathophysiology of diseases [ 1 ]. Despite recent advances in computer simulation [ 1 – 3 ] and other alternative methods [ 4 , 5 ], animal experiments are still necessary to test new treatment strategies in pre-clinical research [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Anesthesia and Monitoring in Small Laboratory Mammals Used in Anesthesiology, Respiratory and Critical Care Research: A Systematic Review on the Current Reporting in Top-10 Impact Factor Ranked Journals

et al. 2015

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RationaleThis study aimed to investigate the quality of reporting of anesthesia and euthanasia in experimental studies in small laboratory mammals published in the top ten impact factor journals.MethodsA descriptive systematic review was conducted and data was abstracted from the ten highest ranked journals with respect to impact factor in the categories ‘Anesthesiology’, ‘Critical Care Medicine’ and ‘Respiratory System’ as defined by the 2012 Journal Citation Reports. Inclusion criteria according to PICOS criteria were as follows: 1) population: small laboratory mammals; 2) intervention: any form of anesthesia and/or euthanasia; 3) comparison: not specified; 4) primary outcome: type of anesthesia, anesthetic agents and type of euthanasia; secondary outcome: animal characteristics, monitoring, mechanical ventilation, fluid management, postoperative pain therapy, animal care approval, sample size calculation and performed interventions; 5) study: experimental studies. Anesthesia, euthanasia, and monitoring were analyzed per performed intervention in each article.ResultsThe search yielded 845 articles with 1,041 interventions of interest. Throughout the manuscripts we found poor quality and frequency of reporting with respect to completeness of data on animal characteristics as well as euthanasia, while anesthesia (732/1041, 70.3%) and interventions without survival (970/1041, 93.2%) per se were frequently reported. Premedication and neuromuscular blocking agents were reported in 169/732 (23.1%) and 38/732 (5.2%) interventions, respectively. Frequency of reporting of analgesia during (117/610, 19.1%) and after painful procedures (38/364, 10.4%) was low. Euthanasia practice was reported as anesthesia (348/501, 69%), transcardial perfusion (37/501, 8%), carbon dioxide (26/501, 6%), decapitation (22/501, 5%), exsanguination (23/501, 5%), other (25/501, 5%) and not specified (20/501, 4%, respectively.ConclusionsThe present systematic review revealed insufficient reporting of anesthesia and euthanasia methods throughout experimental studies in small laboratory mammals. Specific guidelines for anesthesia and euthanasia regimens should be considered to achieve comparability, quality of animal experiments and animal welfare. These measures are of special interest when translating experimental findings to future clinical applications.

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Section: Introductionmentioning

confidence: 99%

Anesthesia and Monitoring in Small Laboratory Mammals Used in Anesthesiology, Respiratory and Critical Care Research: A Systematic Review on the Current Reporting in Top-10 Impact Factor Ranked Journals

et al. 2015

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“…As epilepsy is a disorder with high prevalence of drug resistance, the early recognition of substrates of P-gp will allow us to avoid the selection of candidates with poor bioavailability in the brain. Some of the results obtained from the use of this in silico P-gp filter are already published [52] since they were acquired during the writing of this paper.…”

Section: Discussionmentioning

confidence: 99%

Docking Applied to the Prediction of the Affinity of Compounds to P-Glycoprotein

Palestro

Gavernet

Estiú

et al. 2014

BioMed Research International

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P-glycoprotein (P-gp) is involved in the transport of xenobiotic compounds and responsible for the decrease of the drug accumulation in multi-drug-resistant cells. In this investigation we compare several docking algorithms in order to find the conditions that are able to discriminate between P-gp binders and nonbinders. We built a comprehensive dataset of binders and nonbinders based on a careful analysis of the experimental data available in the literature, trying to overcome the discrepancy noticeable in the experimental results. We found that Autodock Vina flexible docking is the best choice for the tested options. The results will be useful to filter virtual screening results in the rational design of new drugs that are not expected to be expelled by P-gp.

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“…Drugs Selected for Evaluation. The 5 anticonvulsant compounds classified as nonsubstrates by our model ensemble and selected for experimental evaluation were methylparaben (Compound 12, Figure 2), 79 2-(2-oxo-2Hchromen-3-yl)benzoic acid (Compound 1, Figure 2), 1-methyl-1,2,3′,4′-tetrahydro-1′H-spiro[indole-3,2′-quinazoline]-2,4′dione (Compound 16, Figure 2), N-(3,3-dimethylbutan-2-yl)-2-methylfuran-3-carboxamide (Compound 17, Figure 2), 71,72 and N,N′-dibenzylsulfamide (Compound 13, Figure 2). 80 Experimental Model Validation.…”

Section: According Tomentioning

confidence: 99%

Development and Validation of a Computational Model Ensemble for the Early Detection of BCRP/ABCG2 Substrates during the Drug Design Stage

Gantner

Peroni

Morales

et al. 2017

J. Chem. Inf. Model.

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Breast Cancer Resistance Protein (BCRP) is an ATP-dependent efflux transporter linked to the multidrug resistance phenomenon in many diseases such as epilepsy and cancer and a potential source of drug interactions. For these reasons, the early identification of substrates and nonsubstrates of this transporter during the drug discovery stage is of great interest. We have developed a computational nonlinear model ensemble based on conformational independent molecular descriptors using a combined strategy of genetic algorithms, J48 decision tree classifiers, and data fusion. The best model ensemble consists in averaging the ranking of the 12 decision trees that showed the best performance on the training set, which also demonstrated a good performance for the test set. It was experimentally validated using the ex vivo everted rat intestinal sac model. Five anticonvulsant drugs classified as nonsubstrates for BRCP by the model ensemble were experimentally evaluated, and none of them proved to be a BCRP substrate under the experimental conditions used, thus confirming the predictive ability of the model ensemble. The model ensemble reported here is a potentially valuable tool to be used as an in silico ADME filter in computer-aided drug discovery campaigns intended to overcome BCRP-mediated multidrug resistance issues and to prevent drug-drug interactions.

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Several New Diverse Anticonvulsant Agents Discovered in a Virtual Screening Campaign Aimed at Novel Antiepileptic Drugs to Treat Refractory Epilepsy

Cited by 13 publications

References 39 publications

Anesthesia and Monitoring in Small Laboratory Mammals Used in Anesthesiology, Respiratory and Critical Care Research: A Systematic Review on the Current Reporting in Top-10 Impact Factor Ranked Journals

Anesthesia and Monitoring in Small Laboratory Mammals Used in Anesthesiology, Respiratory and Critical Care Research: A Systematic Review on the Current Reporting in Top-10 Impact Factor Ranked Journals

Docking Applied to the Prediction of the Affinity of Compounds to P-Glycoprotein

Development and Validation of a Computational Model Ensemble for the Early Detection of BCRP/ABCG2 Substrates during the Drug Design Stage

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