20XX

HIV-1 integrase core domain in complex with potent allosteric inhibitors

This is a non-PDB format compatible entry.

Summary for 20XX

• Entry DOI: 10.2210/pdb20xx/pdb
• Descriptor: Integrase, (2~{S})-2-[(3~{a}~{R},7~{a}~{R})-1'-ethyl-5'-methyl-spiro[1,3,3~{a},4,5,6,7,7~{a}-octahydroindene-2,3'-indene]-4'-yl]-2-[(2-methylpropan-2-yl)oxy]ethanoic acid, PENTAETHYLENE GLYCOL, ... (5 entities in total)
• Functional Keywords: inhibitor, compplex, viral protein
• Biological source: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
• Total number of polymer chains: 1
• Total formula weight: 19366.72

Authors

Nomura, A.,Orita, T.,Furuzono, T.,Adachi, T. (deposition date: 2025-12-02, release date: 2025-12-31, Last modification date: 2026-04-29)

Primary citation

Adachi, K.,Manabe, T.,Yamasaki, T.,Suma, A.,Ogoshi, Y.,Takahashi, A.,Orita, T.,Nomura, A.,Adachi, T.,Ohata, Y.,Akiyama, Y.,Miyazaki, S.
Discovery and optimization of novel and potent allosteric HIV-1 integrase inhibitors with a spiro[indene] moiety.
Bioorg.Med.Chem., 134:118526-118526, 2026

PubMed Abstract: Allosteric inhibitors of HIV-1 integrase offer a promising approach to block an essential process in HIV-1 replication and offer a new strategy for HIV treatment. During the course of our drug discovery investigations, we identified novel allosteric HIV-1 integrase inhibitor 1 which has a conformationally constrained spiro indane scaffold. Our subsequent medicinal chemistry efforts using a structure-based drug design focused on the efficacies of related compound 5 against not only the wild type enzyme but also enzymes with polymorphisms and resistance mutations. As a result, we identified compound 38 f, which exhibited the desired efficacy against major polymorphisms and resistance mutations (EC(WT) = 0.0040 μM, EC(T124N) = 0.0048 μM, EC(T125A) = 0.0038 μM, EC(A128T) = 0.0057 μM), potent anti-HIV activity in the human serum assay (EC(HS50%) = 0.091 μM), and preferable PK profiles in rats (Cl = 0.017 L/h/kg, MRT = 12.5 h, BA = 71.4 %).

PubMed: 41429097
DOI: 10.1016/j.bmc.2025.118526

Experimental method

X-RAY DIFFRACTION (2.2 Å)