4MFB

Crystal Structure of HIV-1 Reverse Transcriptase in Complex with 8-(2-(2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy)phenoxy)indolizine-2-carbonitrile (JLJ555), a non-nucleoside inhibitor

Summary for 4MFB

• Entry DOI: 10.2210/pdb4mfb/pdb
• Related: 1S9E 4H4M 4H4O 4KKO 4LSL 4LSN
• Descriptor: HIV-1 reverse transcriptase, p66 subunit, HIV-1 reverse transcriptase, p51 subunit, 8-{2-[2-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethoxy]phenoxy}indolizine-2-carbonitrile, ... (4 entities in total)
• Functional Keywords: polymerase, transferase, hydrolase, rnaseh, rnase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus type 1 (HIV-1); More
• Cellular location: Gag-Pol polyprotein: Host cell membrane; Lipid-anchor. Matrix protein p17: Virion membrane; Lipid- anchor . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion . Reverse transcriptase/ribonuclease H: Virion . Integrase: Virion : P03366 P03366
• Total number of polymer chains: 2
• Total formula weight: 114417.10

Authors

Frey, K.M.,Anderson, K.S. (deposition date: 2013-08-27, release date: 2013-11-06, Last modification date: 2023-09-20)

Primary citation

Lee, W.G.,Gallardo-Macias, R.,Frey, K.M.,Spasov, K.A.,Bollini, M.,Anderson, K.S.,Jorgensen, W.L.
Picomolar Inhibitors of HIV Reverse Transcriptase Featuring Bicyclic Replacement of a Cyanovinylphenyl Group.
J.Am.Chem.Soc., 135:16705-16713, 2013

PubMed Abstract: Members of the catechol diether class are highly potent non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs). The most active compounds yield EC50 values below 0.5 nM in assays using human T-cells infected by wild-type HIV-1. However, these compounds such as rilpivirine, the most recently FDA-approved NNRTI, bear a cyanovinylphenyl (CVP) group. This is an uncommon substructure in drugs that gives reactivity concerns. In the present work, computer simulations were used to design bicyclic replacements for the CVP group. The predicted viability of a 2-cyanoindolizinyl alternative was confirmed experimentally and provided compounds with 0.4 nM activity against the wild-type virus. The compounds also performed well with EC50 values of 10 nM against the challenging HIV-1 variant that contains the Lys103Asn/Tyr181Cys double mutation in the RT enzyme. Indolyl and benzofuranyl analogues were also investigated; the most potent compounds in these cases have EC50 values toward wild-type HIV-1 near 10 nM and high-nanomolar activities toward the double-variant. The structural expectations from the modeling were much enhanced by obtaining an X-ray crystal structure at 2.88 Å resolution for the complex of the parent 2-cyanoindolizine 10b and HIV-1 RT. The aqueous solubilities of the most potent indolizine analogues were also measured to be ~40 μg/mL, which is similar to that for the approved drug efavirenz and ~1000-fold greater than for rilpivirine.

PubMed: 24151856
DOI: 10.1021/ja408917n

Experimental method

X-RAY DIFFRACTION (2.88 Å)