8FFX

Crystal structure of HIV-1 reverse transcriptase in complex with non-nucleoside inhibitor 19980

Summary for 8FFX

• Entry DOI: 10.2210/pdb8ffx/pdb
• Descriptor: Reverse transcriptase/ribonuclease H, p51 RT, DIMETHYL SULFOXIDE, ... (7 entities in total)
• Functional Keywords: non nucleotide-reverse transcriptase inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Human immunodeficiency virus type 1 BH10; More
• Total number of polymer chains: 2
• Total formula weight: 114835.54

Authors

Rumrill, S.R.,Ruiz, F.X.,Arnold, E. (deposition date: 2022-12-10, release date: 2023-04-26, Last modification date: 2024-05-22)

Primary citation

Mansouri, M.,Rumrill, S.,Dawson, S.,Johnson, A.,Pinson, J.A.,Gunzburg, M.J.,Latham, C.F.,Barlow, N.,Mbogo, G.W.,Ellenberg, P.,Headey, S.J.,Sluis-Cremer, N.,Tyssen, D.,Bauman, J.D.,Ruiz, F.X.,Arnold, E.,Chalmers, D.K.,Tachedjian, G.
Targeting HIV-1 Reverse Transcriptase Using a Fragment-Based Approach.
Molecules, 28:-, 2023

PubMed Abstract: Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host's immune system leading to acquired immunodeficiency syndrome and potentially death. Although treatments are available to prevent its progression, HIV-1 remains a major burden on health resources worldwide. Continued emergence of drug-resistance mutations drives the need for novel drugs that can inhibit HIV-1 replication through new pathways. The viral protein reverse transcriptase (RT) plays a fundamental role in the HIV-1 replication cycle, and multiple approved medications target this enzyme. In this study, fragment-based drug discovery was used to optimize a previously identified hit fragment (compound ), which bound RT at a novel site. Three series of compounds were synthesized and evaluated for their HIV-1 RT binding and inhibition. These series were designed to investigate different vectors around the initial hit in an attempt to improve inhibitory activity against RT. Our results show that the 4-position of the core scaffold is important for binding of the fragment to RT, and a lead compound with a cyclopropyl substitution was selected and further investigated. Requirements for binding to the NNRTI-binding pocket (NNIBP) and a novel adjacent site were investigated, with lead compound -a minimal but efficient NNRTI-offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors.

PubMed: 37049868
DOI: 10.3390/molecules28073103

Experimental method

X-RAY DIFFRACTION (2.42 Å)