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Evaluation of toxic profile of phenylethylamine entactogens by predicting on- and off-targets and by ADMET and QSAR studies (CROSBI ID 675520)

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Jadrijević-Mladar Takač, Milena ; Takač, Tin Evaluation of toxic profile of phenylethylamine entactogens by predicting on- and off-targets and by ADMET and QSAR studies // Acta Pharmaceutica Hungarica, 3-4 2017, APHGAO 87, (043)85-244. (2017), Hungarian Society for Pharmaceutical Sciences 2017, P1E-8 / Noszal, Bela ; Zelko, Romana (ur.). Budimpešta: Hungarian Society for Pharmaceutical Sciences, 2017. str. 159-160

Podaci o odgovornosti

Jadrijević-Mladar Takač, Milena ; Takač, Tin

engleski

Evaluation of toxic profile of phenylethylamine entactogens by predicting on- and off-targets and by ADMET and QSAR studies

BACKGROUND: A considerable research demonstrates that entactogens have serious toxic effects, both acute and chronic, that resemble those previously seen with other amphetamines. Among many others the four principal types of such serious toxicity are hepatic, cardiovascular, cerebral and hyperpyrexic. AIMS: The aim of this study was to predict on- and off-targets as well as ADMET properties of selected phenylethylamine entactogens (n = 25) in order to get more insights in their toxic profile. RESULT: The sodium dependent serotonin or dopamine transporters and trace amine-associated receptors were revealed by Swiss Target Prediction software as biological targets with the highest probability. Both, CYP inhibitor (1A2, 2D6) and CYP substrate properties (1A2, 2B6, 2C9, 2C19, and 2D6 and 2E1) have been predicted for majority of entactogens. QSAR studies, using computed molecular descriptors (LogP, Mr, TPSA, V) and topological indices (F, X, J, H, WW, W, Wp and Sz) with predicted ADMET properties computed by ADMET PredictorTM 8.1 (Simulations Plus, USA) revealed the most significant correlations between ADMET Risk vs. CYP Risk (R = 0.99), MLogP vs. TOX hERG (cardiotoxicity) and human plasma protein binding (R = 0.75 and R = 0.92, respectively). Predicted ADMET risk were between 1 and 4 (codes 1A, 2C19, 2D6, Mu or Hp), CYP risk between 1 and 2.72 (codes 1A2, 2D6 and 2C19) and TOX risk between 0 and 3.45 with codes of mutagenicity (Mu) and hepatotoxicity (Hp). Mu was predicted for MDMEO or 1-(1, 3-benzodioxol-5-yl)-N-methoxypropan-2-amine (14) and MDOH or 3, 4-methylenedioxy-N-hydroxyamphetamine (15) while both Hp and Mu were predicted for MDCPM or 3, 4-methylenedioxy-N-cyclopropylmethylamphetamine (18). CONCLUSIONS: The results of this study revealed many unfavourable properties of evaluated molecules and MDCPM (18) as entactogen with the worst toxic profile. REFERENCES: 1. Aouidate A. et al., J Taibah Univ Sci 10, 787-96 (2016) 2. LeDonne Jr N et al., J Cheminf 3, 7 (2011)

Entactoges ; Phenylethylamine derivatives ; On- and off-targets, ADMET, Metabolism ; Toxicity ; QSAR

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Podaci o prilogu

159-160.

2017.

objavljeno

Podaci o matičnoj publikaciji

Acta Pharmaceutica Hungarica, 3-4 2017, APHGAO 87, (043)85-244. (2017), Hungarian Society for Pharmaceutical Sciences 2017, P1E-8

Noszal, Bela ; Zelko, Romana

Budimpešta: Hungarian Society for Pharmaceutical Sciences

Podaci o skupu

7th BBBB International Conference on Pharmaceutical Sciences, New Trends in Pharmaceutical Sciences and Pharmacy Practice

poster

05.10.2017-07.10.2017

Balatonfüred, Mađarska

Povezanost rada

Farmacija, Kemija, Kemijsko inženjerstvo