6MCS

X-ray crystal structure of wild type HIV-1 protease in complex with GRL-003

6MCS の概要

• エントリーDOI: 10.2210/pdb6mcs/pdb
• 分子名称: Protease, (3S,3aR,5R,7aS,8S)-hexahydro-4H-3,5-methanofuro[2,3-b]pyran-8-yl [(2S,3R)-4-[{[2-(cyclopropylamino)-1,3-benzothiazol-6-yl]sulfonyl}(2-methylpropyl)amino]-1-(4-fluorophenyl)-3-hydroxybutan-2-yl]carbamate (3 entities in total)
• 機能のキーワード: hiv-1, inhibitor, viral protein
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 11519.61

構造登録者

Bulut, H.,Hayashi, H.,Hattori, S.I.,Aoki, M.,Das, D.,Ghosh, A.K.,Mitsuya, H. (登録日: 2018-09-02, 公開日: 2019-04-24, 最終更新日: 2023-10-11)

主引用文献

Hattori, S.I.,Hayashi, H.,Bulut, H.,Rao, K.V.,Nyalapatla, P.R.,Hasegawa, K.,Aoki, M.,Ghosh, A.K.,Mitsuya, H.
Halogen Bond Interactions of Novel HIV-1 Protease Inhibitors (PI) (GRL-001-15 and GRL-003-15) with the Flap of Protease Are Critical for Their Potent Activity against Wild-Type HIV-1 and Multi-PI-Resistant Variants.
Antimicrob.Agents Chemother., 63:-, 2019

PubMed Abstract: We generated two novel nonpeptidic HIV-1 protease inhibitors (PIs), GRL-001-15 and GRL-003-15, which contain unique crown-like tetrahydropyranofuran (Crn-THF) and P2'-cyclopropyl-aminobenzothiazole (Cp-Abt) moieties as P2 and P2' ligands, respectively. GRL-001-15 and GRL-003-15 have -monofluorophenyl and -monofluorophenyl at the P1 site, respectively, exert highly potent activity against wild-type HIV-1 with 50% effective concentrations (ECs) of 57 and 50 pM, respectively, and have favorable cytotoxicity profiles with 50% cytotoxic concentrations (CCs) of 38 and 11 μM, respectively. The activity of GRL-001-15 against multi-PI-resistant HIV-1 variants was generally greater than that of GRL-003-15. The EC of GRL-001-15 against an HIV-1 variant that was highly resistant to multiple PIs, including darunavir (DRV) (HIV-1), was 0.17 nM, and that of GRL-003-15 was 3.3 nM, while DRV was much less active, with an EC of 216 nM. The emergence of HIV-1 variants resistant to GRL-001-15 and GRL-003-15 was significantly delayed compared to that of variants resistant to selected PIs, including DRV. Structural analyses of wild-type protease (PR) complexed with the novel PIs revealed that GRL-001-15's -fluorine atom forms halogen bond interactions (2.9 and 3.0 Å) with Gly49 and Ile50, respectively, of the protease flap region and with Pro81' (2.7 and 3.2 Å), which is located close to the protease active site, and that two fluorine atoms of GRL-142-13 form multiple halogen bond interactions with Gly49, Ile50, Pro81', Ile82', and Arg8'. In contrast, GRL-003-15 forms halogen bond interactions with Pro81' alone, suggesting that the reduced antiviral activity of GRL-003-15 is due to the loss of the interactions with the flap region.

PubMed: 30962341
DOI: 10.1128/AAC.02635-18

実験手法

X-RAY DIFFRACTION (1.52 Å)