تعتبر ناقلات النيوكليوسيدات البشرية المتوازنة (hENTs) بروتينات مهمة تسمح للنيوكليوسيدات والقواعد النيتروجينيه بالنفاذ إلى الخلية. يعتبر HENT 1 هدفًا واعدًا ضد أمراض القلب وأمراض هنتنغتون حيث أن تثبيطه يترتب عليه تأثيرات علاجية محتملة مثل الحماية من بعض أمراض القلب والأعصاب. ومع ذلك، فإن مثبطات hENT1 المتعارف عليها حاليا لها خصائص دوائية ضعيف، بالتالي بحاجة إلى تطوير مثبطات جديدة. لذلك، قمنا بتطوير بروتوكول حاسوبي له القدرة على تمييز وانتقاء مثبطات hENT1 بطريقة فعالة ومحددة. أولاً، تم إنشاء عدد من فارماكوفور (حامل الخصائص الدوائية) باستخدام مجموعة من المثبطات المعروفة مسبقا. ومن المثير للاهتمام، أن أفضل فارماكوفور للمثبطات قد أظهر معدلات انتقائية وخصوصيه عالية بلغت 92٪ و88٪ على التوالي. إضافة الى ذلك، أدى استخدام مثبط فارماكوفور كمرشح إلى تحسين نتائج الغربلة الافتراضي القائمة على تقنية docking الى ما يقارب الضعف. يمكن أن يكون هذا النهج في تطبيق المحاكاة الحاسوبية (in silico) مفيدًا جدًا في تطوير مثبطات hENT1 جديدة
The human equilibrative nucleoside transporters (hENTs) are important proteins that allow nucleosides and nucleobases permeation into the cell. hENT 1 is a promising target against heart and Huntington’s diseases as its inhibition mediates cardiac- and neural protection effects, respectively. However, the current hENT1 inhibitors have significant off-target effects and poor pharmacological profile, hence there is need for new novel inhibitors. Therefore, we developed a computational protocol that identified and selected inhibitors of hENT1 in an efficient and specific manner. First, several pharmacophores were created using a set of known inhibitors. Consequently, the best inhibitor pharmacophore exhibited as high selectivity and specificity rates as 92% and 88%, respectively. Furthermore, another pharmacophore was validated for the oppositely acting type of the hENT1 molecules (i.e. permeants) to act as an extra refinement step in our search for hENT1 inhibitors. Interestingly, employing the inhibitor pharmacophore as a filter-in along with the permeant pharmacophore as a filter-out resulted in up to two-fold enhancement of docking-based virtual screening results of hENT1 inhibitors. This in silico approach can prove very useful in the development of new cardio- and neuroprotective hENT1 inhibitors.
References used
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Choi JS, Berdis AJ. Nucleoside transporters: biological insights and therapeutic applications. Future Med Chem 2012; 4(11): 1461-78
Noji T, Karasawa A, Kusaka H. Adenosine uptake inhibitors. Eur J Pharmacol 2004; 495(1): 1-16.
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