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Phản ứng phụ của thuốc do biến thể HLA-B*57:01 phổ biến gây ra: Sàng lọc ảo từ DrugBank sử dụng mô phỏng phân tử 3D
Tóm tắt
Các phản ứng phụ bất lợi thuộc kiểu riêng đã được liên kết với khả năng gắn kết của thuốc với protein kháng nguyên bạch cầu người (HLA). Tuy nhiên, do có hàng ngàn biến thể HLA và dữ liệu cấu trúc hạn chế cho các phức hợp thuốc-HLA, việc dự đoán một sự kết hợp thuốc-HLA cụ thể tạo ra một thách thức đáng kể. Gần đây, chúng tôi đã nghiên cứu chế độ liên kết của abacavir với biến thể HLA-B*57:01 bằng cách sử dụng kỹ thuật docking phân tử. Ở đây, chúng tôi đã phát triển một quy trình sàng lọc tập hợp mới gồm ba quy trình docking được lấy từ tinh thể X-ray để sàng lọc cơ sở dữ liệu DrugBank và xác định các loại thuốc có thể liên quan đến HLA-B*57:01. Sau đó, chúng tôi so sánh hiệu suất quy trình của mình với một mô hình khác được phát triển gần đây bởi Metushi và các cộng sự, mô hình này đã đề xuất bảy hoạt chất HLA-B*57:01 in silico, nhưng sau đó đã được xác định là không hoạt động trong thực nghiệm. Sau khi được điều chỉnh, còn lại hơn 6000 loại thuốc đã được phê duyệt và đang thử nghiệm trong DrugBank để tiến hành docking sử dụng các hàm điểm GLIDE SP và XP của Schrodinger. Việc docking được thực hiện với quy trình sàng lọc tập hợp mới của chúng tôi, dựa trên ba tinh thể X-ray khác nhau (3VRI, 3VRJ và 3UPR) khi có và không có các peptide đồng gắn kết. Các chế độ gắn kết của các hợp chất tác động HLA-B*57:01 cho cả ba peptide đã được khám phá thêm bằng cách sử dụng dấu vết tương tác 3D và phân cụm phân cấp. Sàng lọc đã tạo ra 22 hợp chất tác động đã được dự đoán sẽ gắn kết với HLA-B*57:01 trong tất cả các điều kiện docking (SP và XP cùng với và không có các peptide P1, P2 và P3). 22 hợp chất này có độ tương đồng Tanimoto 2D nhỏ hơn 0.6 khi so sánh với cấu trúc của abacavir bản địa, trong khi độ tương đồng chế độ gắn kết 3D của chúng thay đổi trong khoảng rộng hơn (0.2–0.8). Phân cụm phân cấp sử dụng phương pháp Ward Linkage đã tiết lộ các mẫu phân cụm khác nhau cho mỗi peptide đồng gắn kết. Khi chúng tôi thực hiện docking bảy tác nhân đề xuất của Metushi và các cộng sự sử dụng quy trình của chúng tôi, nền tảng sàng lọc của chúng tôi đã xác định sáu trong số bảy là không hoạt động. Mô phỏng động học phân tử đã được sử dụng để khám phá sự ổn định của abacavir và acyclovir trong phức hợp với peptide P3. Nghiên cứu này báo cáo về quá trình docking lớn đối với cơ sở dữ liệu DrugBank và 22 ứng viên có khả năng liên quan đến HLA-B*57:01 mà chúng tôi đã xác định. Quan trọng là, những so sánh giữa nghiên cứu này và nghiên cứu của Metushi và đồng nghiệp đã làm nổi bật những kiến thức mới quan trọng và bổ sung cho sự phát triển của các mô hình in silico cụ thể về HLA trong tương lai.
Từ khóa
#HLA-B*57:01 #phản ứng phụ thuốc #docking phân tử #DrugBank #mô phỏng động lực học phân tửTài liệu tham khảo
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