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مطالعه برهمکنش سه ایزوفرم UDP-گلوکورونوزیل ترانسفراز با مهارکننده های تیروزین کیناز موثر در مقاومت دارویی

نویسندگان

ریحانه چمنی
مریم محمدی
سرور رضایی
الهام میرهاشمی

دانشگاه یزد

https://doi.org/10.22034/11.4.54
چکیده
غیرفعال شدن داروها توسط آنزیم­ها به ویژه UDP-گلوکورونوزیل ترانسفرازها (UGT) یکی از دلایل مقاومت دارویی است. هدف از مطالعه حاضر بررسی برهمکنش آنزیم­های UGT1A3, UGT1A1 و UGT2B7 با مهارکننده­های تیروزین کیناز بود. ساختار آنزیم ها به روش مدلسازی همسانی ساخته شد و ساختار 300 مهارکننده تیروزین کیناز از پایگاه Pubchem دریافت شد. شبیه سازی داکینگ مولکولی به وسیله نرم افزار PyRx 0.8 انجام شد و کمپلکس­ها بر اساس منفی­ترین انرژی اتصال و RMSD صفر مرتب و اسیدآمینه­های درگیر در اتصال بررسی شدند. در مجموع چهل و پنج دارو به عنوان سوبستراهای احتمالی این سه آنزیم­ معرفی شدند. نتایج نشان دادند که محل اتصال این داروها به اسیدآمینه­های جایگاه فعال آنزیم­ها­ بوده و انرژی اتصال لیگاندها به UGT1A1 منفی­تر از دو آنزیم دیگر بود. می­توان پیشنهاد کرد که گلوکورونیداسیون احتمالی این مهارکننده­ها توسط آنزیم­های UGT می­تواند منجر به دو اتفاق مهم شود: اول حذف سریع آنها از گردش خون و ایجاد مقاومت دارویی و دوم جلوگیری از گلوکورنیداسیون بیلی­روبین و افزایش سطح بیلی­روبین سرم. بنابراین بررسی آزمایشگاهی ارتباط بین این مهارکننده­ها و آنزیم­های UGT می­تواند ضروری باشد.

کلیدواژه‌ها

شبیه‌سازی داکینگ مولکولی
آنزیم‌های UGT
مقاومت دارویی
in silico

عنوان مقاله English

Studying the interaction of three isoforms of UDP-glucuronosyltransferase with tyrosine kinase inhibitors effective in drug resistance

نویسنده English

Reyhane Chamani
Yazd University
چکیده English

Deactivation of drugs by enzymes, especially UDP-glucuronosyltransferases (UGT), is a reasons for resistance. The aim of this study was to investigate the interaction of UGT1A3, UGT1A1 and UGT2B7 enzymes with tyrosine kinase inhibitors. The structure of enzymes was made by homology modeling method and the structure of 300 tyrosine kinase inhibitors was obtained from Pubchem database. Molecular docking simulation was performed by PyRx 0.8 software and the complexes were sorted based on the most negative binding energy and zero RMSD and the amino acids involved in the binding were analyzed. In total, forty-five drugs were introduced as possible substrates of these three enzymes. The results showed that the binding site of these drugs were to the amino acids of the active site of the enzymes and the binding energy of the ligands to UGT1A1 was more negative than the other two enzymes. It can be suggested that the possible glucuronidation of these inhibitors by UGT enzymes can lead to two important events: first, their rapid removal from the blood circulation and creating drug resistance, and second, preventing bilirubin glucuronidation and increasing serum bilirubin level. Therefore, laboratory investigation of the relationship between these inhibitors and UGT enzymes can be necessary.

کلیدواژه‌ها English

Molecular docking simulation
UGT enzymes
drug resistance
in silico
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  • تاریخ دریافت 18 خرداد 1405
  • تاریخ انتشار 18 خرداد 1405

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