Sàng lọc in silico, thiết kế phân tử và tổng hợp các hợp chất hóa học có tác dụng ức chế enzym histon deacetylase (HDAC)=In silico screening, design and synthesis of novel inhibitors against histone deacetylase (HDAC)

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Tác giả: Thị Thu Hường Lê, Hải Nam Nguyễn, Thế Hải Phạm

Ngôn ngữ: vie

Ký hiệu phân loại:

Thông tin xuất bản: TC Khoa học Y dược – Đại học Quốc gia Hà Nội, 2018

Mô tả vật lý: tr.20-28

Bộ sưu tập: Metadata

ID: 474446

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Finding a new treatment for cancer is one of the most interested fields for pharmaceutical research worldwide. As a member of HDAC class I, histone deacetylase 2 (HDAC2) appears to be an important druggable target. Today, computer-aided drug design is increasingly used in the drug discovery and development processes. In this study, computational methods, including Quantitative Structure-Activity Relationship and Molecular Docking approaches, have been explored for virtual screening as well as rational design of potential inhibitors of HDAC enzymes. The main results included the identification of 3 novel structure scaffolds, which had never been studied in anti- HDAC or anticancer activities. In particular, ibandronic acid showed very good half-maximal inhibitory concentration against HDAC extracted f-rom MCF-7 cell line (IC50 of 15 μM) and citotoxicity of <
50 μM against three cancer cell lines (MCF-7, LNCaP, and SK-LU-1). On the other hand, six novel series of HDAC2 inhibitors were rationally designed using molecular descriptors derived f-rom ISIDA fragmentor methodology. A series of novel hydroxamates incorporating oxoindoline aromatic system was synthesized and evaluated in the inhibitory activity against HDAC2 enzyme. The results showed that three synthesized compounds (4a-c) exhibited very good inhibitory potency, with IC50 ranged f-rom 1.70-6.24 μM
notably, compound 4a displayed similar potency to that of Vorinostat (SAHA), a commercial drug currently used in the management of cutaneous T cell lymphoma. Physicochemical and molecular simulation profiling assays suggested that this compound was drug-like and suitable for further study towards developing it into new anti-cancer drug.Nghiên cứu thuốc điều trị ung thư mới hiện nay đang là mối quan tâm hàng đầu của thế giới. Một trong số các mục tiêu phân tử đáng chú ý là enzym Histon Deacetylase (HDAC). Hiện nay, khoa học máy tính ngày càng được sử dụng rộng rãi trong tìm kiếm và phát triển thuốc mới. Trong nghiên cứu này, các công cụ máy tính, bao gồm các mô hình liên quan định lượng cấu trúctác dụng (QSAR) và phương pháp mô phỏng phân tử docking đã được sử dụng để thiết kế và sàng lọc nhằm tìm kiếm các hợp chất hoá học mới, có hoạt tính ức chế mạnh enzyme HDAC2, có tiềm năng để phát triển thành thuốc chống ung thư. Kết quả quan trọng nhất của đề tài là đã sàng lọc tìm được 3 nhóm cấu trúc mới, chưa từng được nghiên cứu tác dụng trên đích HDAC cũng như tác dụng kháng ung thư. Trong đó hợp chất acid ibandronic này ức chế 50% hoạt tính của enzym HDAC chiết từ tế bào ung thư vú ở nồng độ 15 μM và có độc tính tế bào mạnh ở mức nồng độ <
50 μM trên 3 dòng tế bào ung thư (vú, tiền liệt tuyến và phổi). Ứng dụng phương pháp thiết kế cấu trúc phân mảnh ISIDA, 6 dãy dẫn chất của acid hydroxamic mới được thiết kế. Trong đó hợp chất tích hợp nhân oxoindolin được lựa chọn để tổng hợp và thử hoạt tính ức chế HDAC2. Kết quả cho thấy 3 hợp chất được tổng hợp có hoạt tính ức chế enzym IC50 từ 1,70-6,24 μM. Đặc biệt hợp chất 4a có hoạt tính mạnh tương đương với một thuốc ức chế HDAC mạnh hiện đang lưu hành trên thị trường là Vorinostat (SAHA). Nghiên cứu đặc điểm lý hoá cũng như mô phỏng phân tử cho thấy các hợp chất này có đặc điểm giống thuốc phù hợp cho nghiên cứu sâu hơn nhằm phát triển thành thuốc chống ung thư mới trong tương lai.

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