Summary for 9YRR
| Entry DOI | 10.2210/pdb9yrr/pdb |
| Descriptor | Protease, (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl {(2S,3R)-1-(3,5-difluorophenyl)-3-hydroxy-4-[{4-[(1S)-1-hydroxyethyl]benzene-1-sulfonyl}(2-methylpropyl)amino]butan-2-yl}carbamate, SULFATE ION, ... (4 entities in total) |
| Functional Keywords | hiv, nl4-3 protease, drug resistance, protease inhibitor, complex, hydrolase inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor |
| Biological source | Human immunodeficiency virus 1 |
| Total number of polymer chains | 2 |
| Total formula weight | 22564.54 |
| Authors | Lockbaum, G.J.,Kaur, J.,Shaqra, A.M.,Schiffer, C.A. (deposition date: 2025-10-17, release date: 2025-12-24, Last modification date: 2026-01-07) |
| Primary citation | Kaur, J.,Spielvogel, E.,Nageswara Rao, D.,Rusere, L.N.,Shaqra, A.M.,Lockbaum, G.J.,Maryam, A.,Yilmaz, N.K.,Swanstrom, R.,Schiffer, C.A.,Ali, A. Fluorinated HIV-1 protease inhibitors containing chiral hydroxyethylbenzene and indanol as P2' ligands with potent activity against drug-resistant variants. Eur.J.Med.Chem., 304:118510-118510, 2025 Cited by PubMed Abstract: HIV-1 protease inhibitors are potent antiretroviral drugs, but their efficacy is often undermined by poor pharmacokinetics and drug resistance. Here, we employed a structure-guided design strategy to improve the potency and resistance profile of HIV-1 protease inhibitors by optimizing hydrogen bonding and van der Waals interactions within the protease substrate envelope. A series of darunavir analogs were designed by incorporating chiral 4-(1-hydroxyethyl)benzene and 1-indanol moieties as P2' ligands, in combination with P1 fluorination. The resulting compounds showed distinct potency profiles depending on the conformational flexibility of the P2' hydroxyl group. Notably, the P1 fluorinated compounds exhibited excellent antiviral potency against highly drug-resistant HIV-1 variants. Analysis of the protease-inhibitor cocrystal structures revealed that, similar to the 4-(1-hydroxyethyl)benzene moiety, both stereoisomers of the 1-indanol moiety make direct hydrogen bonding interactions with the backbone NH of Asp30'. To maintain polar interactions in the S2' subsite of HIV-1 protease, the orientation of the (R)-indanol moiety was flipped relative to the (S)-1-indanol moiety. The SAR data and structural analysis offer insights for further optimization to improve potency against drug-resistant HIV-1 variants. PubMed: 41448052DOI: 10.1016/j.ejmech.2025.118510 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.89 Å) |
Structure validation
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