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بررسی مهارکنندگی ترکیب طبیعی Phellopterin بر پروتئاز OTU ویروس تب خونریزی‌دهنده کریمه-کنگو با رویکردهای محاسباتی | ||
| فصلنامه علمی زیست شناسی جانوری تجربی | ||
| دوره 13، شماره 4 - شماره پیاپی 52، آبان 1404، صفحه 13-27 اصل مقاله (2.06 M) | ||
| نوع مقاله: مقاله پژوهشی | ||
| شناسه دیجیتال (DOI): 10.30473/eab.2025.74787.1996 | ||
| نویسنده | ||
| سمیه فرهمند* | ||
| گروه زیست شناسی، دانشگاه پیام نور، تهران، ایران | ||
| چکیده | ||
| تب خونریزی‌دهندۀ کریمه–کنگو (CCHF) یک بیماری ویروسی زئونوز با مرگ‌ومیر بالاست که تاکنون درمان اختصاصی مؤثری برای آن معرفی نشده است. ویروس عامل بیماری، از جنس Nairovirus و خانواده Orthonairoviridae بوده و قطعه L ژنوم آن پلی‌پروتئینی را رمزگذاری می‌کند که حاوی آنزیم RNA-dependent RNA polymerase (RdRp) و دامنه پروتئازی OTU در بخش N-terminal است. دامنه OTU با فعالیت دی‌یوبی‌کوئیتینازی (DUB)، در سرکوب ایمنی میزبان نقش دارد و به‌دلیل توالی نسبتاً محافظت‌شده‌اش، هدفی مناسب برای طراحی داروهای ضدویروسی به‌شمار می‌رود. این پژوهش با هدف بررسی اثر مهاری ترکیب طبیعی Phellopterin (Phe) از گیاه Heracleum persicum بر دامنه OTU انجام شد؛ ترکیبی با ساختار فوروکومارینی مشابه مهارکننده‌های شناخته‌شده و برگزیده از میان ۵۰ لیگاند بر پایه انرژی اتصال و ویژگی‌های .ADMET ساختار بلورینOTU (PDB ID: 3PRP) پس از آماده‌سازی، با استفاده از نرم‌افزار AutoDock 4.0 مورد داکینگ قرار گرفت و کمپلکس حاصل طی شبیه‌سازی دینامیک مولکولی 150 نانوثانیه‌ای با روش‌های GROMACS بررسی شد. Phellopterin با انرژی اتصال مناسب (ΔG=-8.1 kcal/mol) به ناحیه ورودی جایگاه فعال متصل شده و تعاملات پایداری با باقی‌مانده‌هایی نظیر Ala79–Leu86 برقرار کرد، که این اتصال با تثبیت ساختار و انسداد نسبی مسیر فعال، می‌تواند موجب مهار غیررقابتی عملکرد آنزیم گردد. تحلیل‌های RMSD، RMSF، Rg، پیوندهای هیدروژنی و PCA، پایداری ساختاری کمپلکس را تأیید کردند. بررسی ADMET نیز پروفایل فارماکوکینتیکی، جذب خوراکی، نفوذپذیری سلولی و ایمنی مناسبی برای ترکیب نشان داد. بر این اساس، Phellopterin می‌تواند به‌عنوان مهارکننده بالقوه OTU ویروس CCHFV مطرح شود و زمینه‌ساز طراحی داروهای ضدویروسی طبیعی و مؤثر باشد؛ اگرچه تأیید این نتایج مستلزم مطالعات تجربی in vitro و in vivo است. | ||
| کلیدواژه‌ها | ||
| ویروس تب خونریزی‌دهنده کریمه-کنگو؛ Phellopterin؛ RNA پلی‌مراز وابسته به RNA؛ شبیه‌سازی داکینگ مولکولی؛ فوروکومارین‌ها | ||
| عنوان مقاله [English] | ||
| Computational investigation of the inhibitory potential of the natural compound phellopterin against the OTU protease of crimean-congo hemorrhagic fever virus | ||
| نویسندگان [English] | ||
| Somayeh Farahmand | ||
| Department of Biology, Payame Noor University, Tehran, Iran | ||
| چکیده [English] | ||
| Crimean-Congo Hemorrhagic Fever (CCHF) is a zoonotic viral disease with high mortality, for which no specific and effective treatment has yet been introduced. The causative virus, classified within the Nairovirus genus and Orthonairoviridae family, encodes a polyprotein via its L segment, which includes the RNA-dependent RNA polymerase (RdRp) and an N-terminal OTU protease domain. The OTU domain, through its deubiquitinase (DUB) activity, plays a role in suppressing the host immune response and, due to its relatively conserved sequence, represents a promising target for antiviral drug design. This study aimed to evaluate the inhibitory effect of the natural compound Phellopterin (Phe), derived from Heracleum persicum, on the OTU domain. The crystal structure of OTU (PDB ID: 3PRP) was prepared and subjected to molecular docking using AutoDock 4.0. The top-ranked complex was then analyzed via a 150-nanosecond molecular dynamics (MD) simulation using GROMACS. Phellopterin showed a favorable binding affinity (ΔG = –8.1 kcal/mol) and formed stable interactions with residues such as Ala79–Leu86 near the active-site entry. Analyses including RMSD, RMSF, Rg, hydrogen bonding, and PCA confirmed the structural stability of the complex. ADMET evaluation also indicated desirable pharmacokinetic properties, oral absorption, cellular permeability, and safety. Altogether, Phellopterin may serve as a potential inhibitor of the CCHFV OTU protease and provide a foundation for the development of effective natural antiviral agents. | ||
| کلیدواژه‌ها [English] | ||
| Crimean-Congo Hemorrhagic Fever virus, Furanocoumarins, Molecular docking simulation, Phellopterin, RNA-dependent RNA polymerase | ||
| مراجع | ||
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آمار تعداد مشاهده مقاله: 13 تعداد دریافت فایل اصل مقاله: 12 |
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