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Truy cập
Đang online: 4
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CHI TIẾT
Nghiên cứu xây dựng mô hình sàng lọc ảo trên các chất ức chế ABCG2
Virtual screening for identification of inhibitors
Lê Minh Trí, Hoàng Viết Nhâm, Trần Quế Hương, Đỗ Trần Giang Sơn, Nguyễn Hoàng Minh, Nguyễn Thị Thu Hạnh, Nguyễn Thị Ánh Tuyết, Đỗ Minh Nguyệt, Thái Khắc Minh
Số: 526 - Tháng 2/2020 - Trang 2-8

Hiện tượng đề kháng đa thuốc (MDR) ở các bệnh nhân ung thư kể cả đối với các thuốc có cấu trúc và chức năng khác nhau là nguyên nhân dẫn đến thất bại điều trị trên lâm sàng. Trong đó, hoạt động của các bơm vận chuyển ngược của nhóm protein màng ABC liên quan mật thiết tới nguồn gốc của hiện tượng đa kháng này. ABCG2/BCRP là bơm vận chuyển thứ 2 thuộc phân họ G, trong họ bơm vận chuyển thuốc ABC. ABCG2 đóng vai trò như một kênh thải chất độc cho tế bào, biểu hiện nhiều ở ruột, gan, thận, mô ung thư làm làm giảm sinh khả dụng của thuốc. Đồng thời ở những tế bào ung thư việc tăng biểu hiện của ABCG2 dẫn đến thất bại trị liệu. Để khắc phục hiện tượng này, việc tìm ra các tác nhân ức chế ABCG2 là thiết yếu. Tuy nhiên, việc tìm kiếm một chất ức chế mới là một quá trình lâu dài và tốn kém, vậy nên việc xây dựng các mô hình sàng lọc ảo đang là vấn đề được quan tâm hiện nay. Với hy vọng ứng dụng trong sàng lọc số lượng lớn các chất có sẵn trong ngân hàng dữ liệu, định hướng thiết kế và tổng hợp nhằm mục đích giải thích cơ chế tác động cũng như tìm ra những chất ức chế ABCG2. Các mô hình này cho phép tìm kiếm nhanh các cấu trúc có khả năng gắn kết cao vào đích tác động từ một ngân hàng dữ liệu lớn của rất nhiều hợp chất hóa học. Nghiên cứu xây dựng mô hình sàng lọc ảo trên các chất ức chế ABCG2 được thực hiện với các nội dung: (i) Xây dựng mô hình pharmacophore từ các chất có hoạt tính ức chế mạnh bơm ABCG2; (ii) Xây dựng được mô hình mô tả phân tử docking các chất ức chế bơm ABCG2; (iii) Tiến hành sàng lọc các chất ức chế bơm ABCG2 trên tập drugbank và tập TCM.

Phương pháp nghiên cứu

Do cấu trúc kết tinh tinh thể của protein ABCG2 vẫn chưa được xác định, nên phương pháp xây dựng mô hình pharmacophore dựa trên ligand vẫn giữ vai trò chủ đạo.

Kết luận

Nghiên cứu này đã xây dựng được mô hình sàng lọc các chất ức chế mạnh bơm ABCG2 dựa trên 2 mô hình là mô hình pharmacophore trên các chất ức chế mạnh ABCG2 và mô hình mô tả phân tử docking xây dựng trên mô hình protein homology ABCG2; và đã tiến hành ứng dụng sàng lọc các chất ức chế trên 2 tập chất là Drugbank và TCM. Trong nghiên cứu này, mô hình pharmacophore được xây dựng dựa trên các chất có hoạt tính ức chế mạnh. Mô hình bơm vừa được xây dựng được áp dụng để tiến hành docking với các chất có hoạt tính ức chế. Kết quả docking cho thấy các chất này có ái lực gắn kết cao với khoang trung tâm (93,54 % các chất có điểm số docking nhỏ hơn hoặc bằng - 10 KJ/mol) và những acid amin Gln 181, Phe 182, Asn 391, Gln 393, Glu 446, Ser 443, Val 533, Val 534, Val536, Leu 539 là những acid amin có quan trọng trong khoang gắn kết trong đó 2 acid amin Gln 393, Asn 391 là 2 acid amin có mặt trong hầu hết các liên kết hydro tạo ra giữa khoang gắn kết vào chất ức chế. Trước khi có cấu trúc có độ phân giải tốt hơn của bơm ABCG2 thì mô hình docking trên protein tạo ra từ kỹ thuật tương đồng này có thể sử dụng để dự đoán các chất có tiềm năng ức chế ABCG2. Các chất cho kết quả tốt khi sàng qua mô hình này có thể ưu tiên tổng hợp hoặc chiết xuất và thử hoạt tính sinh học.

With regard for the purpose of minimising the multi-drug resistance and improving the bioavailability to provide better therapeutic results, the discovery of the ATP Binding Cassette subfamily G member 2 (ABCG2) inhibitor is necessary, the virtual screening process was performed on in silico models, namely pharmacophore modelling and molecular docking, and thereby, two  pharmacophore models on strong ABCG2 inhibitors and molecular docking models on protein homology model ABCG2 were built. Further, these models were used to screen for ABCG2 inhibitors on TCM and Drugbank libraries to find out new ABCG2 inhibitors.

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