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Sự biến đổi phân tử trong độ nhạy thuốc chống lại protease HIV-1 phân nhóm B và C-SA: Nghiên cứu MD
Tóm tắt
Protease HIV-1 (HIV PR) là một trong những mục tiêu hứa hẹn nhất cho nghiên cứu phát triển thuốc chống HIV. Nghiên cứu phát triển thuốc chống HIV đã tập trung nhiều vào protease HIV-1 phân nhóm B, mặc dù các chất ức chế protease (PIs) được FDA phê duyệt thường có hoạt động sinh học thay đổi đối với các phân nhóm protease khác như protease phân nhóm C (C-SA) phổ biến ở khu vực phía nam Sahara. Các báo cáo thí nghiệm gần đây nhấn mạnh sự khác biệt trong hành vi động lực học giữa hai phân nhóm protease này. Trong nghiên cứu này, động lực học của ba PIs được FDA phê duyệt, cụ thể là atazanavir (ATV), darunavir (DRV), và ritonavir (RTV), đã được phân tích kỹ lưỡng cho cả hai phức hợp protease phân nhóm B và C bằng cách sử dụng mô phỏng động lực học phân tử (MD) trong dung môi rõ ràng. Các phân tích MD sau so sánh thông qua động lực flap, phân tích tương quan chéo, phân tích thành phần chính (PCA), phân tích phân rã theo từng dư lượng, và phân tích năng lượng tự do liên kết MM-GBSA đã tiết lộ những phản ứng thay đổi được quan sát trong các phức hợp của các PIs này trong hai phân nhóm protease này. Các phân tích năng lượng liên kết lý thuyết được tính toán phù hợp với các thí nghiệm ở mức độ đáng kể. Năng lượng liên kết lý thuyết kết hợp với động lực flap có vẻ tương ứng với độ nhạy thuốc thay đổi đối với protease HIV-1 phân nhóm B và C-SA. Các phân tích hiện tại cung cấp cái nhìn hữu ích về cơ chế hoạt động của các PIs chống lại hai phân nhóm protease HIV-1 khác nhau này, điều này sẽ giúp phát triển các hợp chất chống protease mới.
Từ khóa
#HIV-1 #protease #atazanavir #darunavir #ritonavir #động lực học phân tử #phân tích năng lượng tự doTài liệu tham khảo
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