6AOC

Crystal Structure of an N-Hydroxythienopyrimidine-2,4-dione RNase H Active Site Inhibitor with Multiple Binding Modes to HIV Reverse Transcriptase

6AOC の概要

• エントリーDOI: 10.2210/pdb6aoc/pdb
• 分子名称: Reverse transcriptase/ribonuclease H, p51 RT, MANGANESE (II) ION, ... (7 entities in total)
• 機能のキーワード: hiv-1, transferase - transferase inhibitor complex, transferase / transferase inhibitor
• 由来する生物種: Human immunodeficiency virus type 1 group M subtype B (isolate BH10) (HIV-1); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 234444.14

構造登録者

Kirby, K.A.,Sarafianos, S.G. (登録日: 2017-08-15, 公開日: 2018-08-08, 最終更新日: 2023-10-04)

主引用文献

Kankanala, J.,Kirby, K.A.,Huber, A.D.,Casey, M.C.,Wilson, D.J.,Sarafianos, S.G.,Wang, Z.
Design, synthesis and biological evaluations of N-Hydroxy thienopyrimidine-2,4-diones as inhibitors of HIV reverse transcriptase-associated RNase H.
Eur J Med Chem, 141:149-161, 2017

PubMed Abstract: Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only HIV enzymatic function not targeted by current antiviral drugs. Although various chemotypes have been reported to inhibit HIV RNase H, few have shown significant antiviral activities. We report herein the design, synthesis and biological evaluation of a novel N-hydroxy thienopyrimidine-2,3-dione chemotype (11) which potently and selectively inhibited RNase H with considerable potency against HIV-1 in cell culture. Current structure-activity-relationship (SAR) identified analogue 11d as a nanomolar inhibitor of RNase H (IC = 0.04 μM) with decent antiviral potency (EC = 7.4 μM) and no cytotoxicity (CC > 100 μM). In extended biochemical assays compound 11d did not inhibit RT polymerase (pol) while inhibiting integrase strand transfer (INST) with 53 fold lower potency (IC = 2.1 μM) than RNase H inhibition. Crystallographic and molecular modeling studies confirmed the RNase H active site binding mode.

PubMed: 29031062
DOI: 10.1016/j.ejmech.2017.09.054

実験手法

X-RAY DIFFRACTION (1.8 Å)