6AOC

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

Summary for 6AOC

• Entry DOI: 10.2210/pdb6aoc/pdb
• Descriptor: Reverse transcriptase/ribonuclease H, p51 RT, MANGANESE (II) ION, ... (7 entities in total)
• Functional Keywords: hiv-1, transferase - transferase inhibitor complex, transferase / transferase inhibitor
• Biological source: Human immunodeficiency virus type 1 group M subtype B (isolate BH10) (HIV-1); More
• Total number of polymer chains: 4
• Total formula weight: 234444.14

Authors

Kirby, K.A.,Sarafianos, S.G. (deposition date: 2017-08-15, release date: 2018-08-08, Last modification date: 2023-10-04)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)