8FE8

Crystal Structure of HIV-1 RT in Complex with the non-nucleoside inhibitor 18b1

Summary for 8FE8

• Entry DOI: 10.2210/pdb8fe8/pdb
• Descriptor: Reverse transcriptase/ribonuclease H, Reverse transcriptase p51, 5-[(4-{4-[(E)-2-cyanoethenyl]-2,6-dimethylphenoxy}pyrimidin-2-yl)amino]-2-[4-(methanesulfonyl)piperazin-1-yl]benzonitrile, ... (6 entities in total)
• Functional Keywords: non nucleotide-reverse transcriptase inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 2
• Total formula weight: 115253.84

Authors

Rumrill, S.,Ruiz, F.X.,Arnold, E. (deposition date: 2022-12-05, release date: 2023-10-18)

Primary citation

Jiang, X.,Huang, B.,Rumrill, S.,Pople, D.,Zalloum, W.A.,Kang, D.,Zhao, F.,Ji, X.,Gao, Z.,Hu, L.,Wang, Z.,Xie, M.,De Clercq, E.,Ruiz, F.X.,Arnold, E.,Pannecouque, C.,Liu, X.,Zhan, P.
Discovery of diarylpyrimidine derivatives bearing piperazine sulfonyl as potent HIV-1 nonnucleoside reverse transcriptase inhibitors.
Commun Chem, 6:83-83, 2023

PubMed Abstract: HIV-1 reverse transcriptase is one of the most attractive targets for the treatment of AIDS. However, the rapid emergence of drug-resistant strains and unsatisfactory drug-like properties seriously limit the clinical application of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Here we show that a series of piperazine sulfonyl-bearing diarylpyrimidine-based NNRTIs were designed to improve the potency against wild-type and NNRTI-resistant strains by enhancing backbone-binding interactions. Among them, compound 18b1 demonstrates single-digit nanomolar potency against the wild-type and five mutant HIV-1 strains, which is significantly better than the approved drug etravirine. The co-crystal structure analysis and molecular dynamics simulation studies were conducted to explain the broad-spectrum inhibitory activity of 18b1 against reverse transcriptase variants. Besides, compound 18b1 demonstrates improved water solubility, cytochrome P450 liability, and other pharmacokinetic properties compared to the currently approved diarylpyrimidine (DAPY) NNRTIs. Therefore, we consider compound 18b1 a potential lead compound worthy of further study.

PubMed: 37120482
DOI: 10.1038/s42004-023-00888-4

Experimental method

X-RAY DIFFRACTION (2.5 Å)