7LQU

Crystal Structure of HIV-1 RT in Complex with NBD-14075

Summary for 7LQU

• Entry DOI: 10.2210/pdb7lqu/pdb
• Descriptor: Reverse transcriptase p66, Reverse transcriptase p51, ~{N}-[(1~{R})-2-azanyl-1-[5-(hydroxymethyl)-1,3-thiazol-2-yl]ethyl]-5-(4-chloranyl-3-fluoranyl-phenyl)-1~{H}-pyrrole-2-carboxamide, ... (5 entities in total)
• Functional Keywords: human immunodeficiency virus 1, non nucleotide-reverse transcriptase inhibitor, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Human immunodeficiency virus type 1 (HIV-1); More
• Total number of polymer chains: 2
• Total formula weight: 114768.82

Authors

Losada, N.,Ruiz, F.X.,Gruber, K.,Das, K.,Arnold, E. (deposition date: 2021-02-15, release date: 2021-11-17, Last modification date: 2023-10-18)

Primary citation

Losada, N.,Ruiz, F.X.,Curreli, F.,Gruber, K.,Pilch, A.,Das, K.,Debnath, A.K.,Arnold, E.
HIV-1 gp120 Antagonists Also Inhibit HIV-1 Reverse Transcriptase by Bridging the NNRTI and NRTI Sites.
J.Med.Chem., 64:16530-16540, 2021

PubMed Abstract: HIV-1 infection is typically treated using ≥2 drugs, including at least one HIV-1 reverse transcriptase (RT) inhibitor. Drugs targeting RT comprise nucleos(t)ide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). NRTI-triphosphates bind at the polymerase active site and, following incorporation, inhibit DNA elongation. NNRTIs bind at an allosteric pocket ∼10 Å away from the polymerase active site. This study focuses on compounds ("NBD derivatives") originally developed to bind to HIV-1 gp120, some of which inhibit RT. We have determined crystal structures of three NBD compounds in complex with HIV-1 RT, correlating with RT enzyme inhibition and antiviral activity, to develop structure-activity relationships. Intriguingly, these compounds bridge the dNTP and NNRTI-binding sites and inhibit the polymerase activity of RT in the enzymatic assays (IC < 5 μM). Two of the lead compounds, NBD-14189 and NBD-14270, show potent antiviral activity (EC < 200 nM), and NBD-14270 shows low cytotoxicity (CC > 100 μM).

PubMed: 34735153
DOI: 10.1021/acs.jmedchem.1c01104

Experimental method

X-RAY DIFFRACTION (2.6 Å)