Naslov
QSAR Studies of Impact of Structural Features of Benzodiazepines on their Toxicity

Autori
Jadrijević-Mladar Takač, Milena ; Pajazetović, Esad ; Takač, Vedran

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Knjiga sažetaka, 5. Hrvatski kongres farmacije s međunarodnim sudjelovanjem 'Farmaceutska izvrsnost u službi zdravlja'/ Book of Abstracts, 5th Croatian Congress on Pharmacy with International Participation 'Pharmaceutical Excellence Dedicated to Health' / Zorc, Branka - Samobor : Hrvatsko farmaceutsko društvo, 2015, 180-180

ISBN
978-953-7897-05-5

Skup
5. Hrvatski kongres farmacije s međunarodnim sudjelovanjem 'Farmaceutska izvrsnost u službi zdravlja'/5th Croatian Congress on Pharmacy with International Participation 'Pharmaceutical Excellence Dedicated to Health'

Mjesto i datum
Rovinj, Hrvatska, 21.05.2015. - 24.05.2015

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
Benzodiazepines; toxicity; molecular descriptors; drug-likeness; ADMET; QSAR

Sažetak
Benzodiazepines (BDZs) are drugs with common molecular structure (benzene ring fused with heterocyclic diazepine ring) and similar pharmacological activities, including antianxiety, muscle relaxing, anticonvulsive and sedative-hypnotic effects. BDZs selectively bind to the gamma subunit of the GABA-A receptor.on gamma-aminobutyric acid-A (GABA-A) receptors, thus enhance the opening of GABA-activated chloride channels. Benzodiazepines are generally viewed as safe and effective drugs for short-term use while long-term use is controversial due to concerns about adverse psychological and physical effects, decreasing effectiveness, and physical dependence and withdrawal. There is also controversy concerning the safety of benzodiazepines in pregnancy. The present paper, aimed at obtaining a deeper insight into structure-property and structure activity and toxicity relationships of this class of drugs, reports the results of correlation studies between computed molecular descriptors (MDs), topological indices (TIs), drug-likeness scores (DLs) and predicted ADMET parameters of toxicity in a series of benzodiazepines (n = 38) that are in clinical use. MDs and DLs of investigated BDZs were calculated using Molinspiration engines v2013.09 and v2011.06. TIs were computed using Chemicalize.org/Properties Viewer and ADMET properties were predicted by MedChem StudioTM and ADMET PredictorTM 7.0 (Simulations Plus, Inc., USA). Analyses were performed by OriginPro 8.0 (Origin Laboratories, USA). Significant correlations between predicted TOX BRM Rat and TOX BRM Mouse parameters which represent a dose of test compound to induce tumors in rats and mice, respectively, were revealed with MDs (R = 0.8057 to 0.9226) and TIs (R = -0.8016 to -0.8966). Obtained results suggest that the BDZ toxicity decreases with increase of BDZ molecule. The collinear relationship (R = -0.8267) between TOX BRM Mouse and MlogP were also revealed The results of correlation studies between TOX BRM Rat and GPCR ligand-likeness (GPCRs l DLs, R = -0.8772) as well as ion channel modulator (ICM DLs, R = -0.9277) indicate that the toxicity of benzodiazepines increases with the increase of GPCR l DLs and ICM DLs. The ADMET Risks were computed in the range from 1 (diazepam) to 7.566 (quazepam), CYP Risks between 0 (most of BDZs) and 1.429 (quazepam), TOX Risks between 1 (most of BDZs) and 4.08 (loprazolam), while significant TOX hERG parameters were computed for the majority of BDZs. For tricyclic triazole-BZDs and alprazolam (category D), estazolam and triazolam (category X) extremely high values of TOX BRM Mouse and significant GPCR l DLs and ICM DLs were computed, while highest values of TOX BRM Rat were computed for halazepam (category D) and quazepam (category X) and significant nuclear receptor ligand-likeness (NRL DLs). Keywords: Benzodiazepines, toxicity, molecular descriptors, drug-likeness, ADMET, QSAR Reference: 1. Hadjipavlou-Litina D, Hansch C (1994) Quantitative Structure-Activity Relationships of the Benzodiazepines. A Review and Reevaluation. Chem. Rev. 94 (6): 1483–1505.

Izvorni jezik
Engleski

Znanstvena područja
Farmacija

Napomena
BM048 - Potpora Sveučilišta u Zagrebu, Biomedicinsko područje, projekt 'Istraživanje značajki inhibitora protein tirozin kinaze i histon deacetilaze u antitumorskoj terapiji' (voditelj M. Jadrijević-Mladar Takač)

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