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. 2010 Nov 8;5(11):1850-4.

doi: 10.1002/cmdc.201000318.

Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors

Arun K Ghosh¹, Chun-Xiao Xu, Kalapala Venkateswara Rao, Abigail Baldridge, Johnson Agniswamy, Yuan-Fang Wang, Irene T Weber, Manabu Aoki, Salcedo Gomez Pedro Miguel, Masayuki Amano, Hiroaki Mitsuya

Affiliations

PMID: 20827746
PMCID: PMC3523686
DOI: 10.1002/cmdc.201000318

Probing multidrug-resistance and protein-ligand interactions with oxatricyclic designed ligands in HIV-1 protease inhibitors

Arun K Ghosh et al. ChemMedChem. 2010.

. 2010 Nov 8;5(11):1850-4.

doi: 10.1002/cmdc.201000318.

Authors

Arun K Ghosh¹, Chun-Xiao Xu, Kalapala Venkateswara Rao, Abigail Baldridge, Johnson Agniswamy, Yuan-Fang Wang, Irene T Weber, Manabu Aoki, Salcedo Gomez Pedro Miguel, Masayuki Amano, Hiroaki Mitsuya

Affiliation

¹ Department of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA. akghosh@purdue.edu

PMID: 20827746
PMCID: PMC3523686
DOI: 10.1002/cmdc.201000318

No abstract available

PubMed Disclaimer

Figures

Figure 1
Structure of darunavir (1) and PIs 2–4.

Figure 2
Inhibition of HIV-1 protease dimerization by GRL-0519A. Changes in emission intensity ratios in the presence of DRV or GRL-0519A are shown. COS7 cells were co-transfected with a pair of HIV-PR^CFP and HIV-PR^YFP, and CFP^A/B ratios were determined. The mean values of the ratios are shown as bars. The results of statistical evaluation of the changes in the CFP^A/B ratios determined in the presence or absence of DRV or GRL-0519A are as follows: the CFP^A/B ratios in the absence of drug (CFP^A/B_{No Drug}) vs the CFP^A/B ratios in the presence of 0.001 µM DRV (CFP^A/B_{0.001 DRV}), p=0.94; CFP^A/B_{No Drug} vs CFP^A/B_{0.01 DRV}, p=0.15; CFP^A/B_{No Drug} vs CFP^A/B_{0.1 DRV}, p=0.0042; CFP^A/B_{No Drug} vs CFP^A/B_{1.0 DRV}, p=0.0004; CFP^A/B_{No Drug} vs CFP^A/B_{0.001 GRL-519}, p=0.947; CFP^A/B_{No Drug} vs CFP^A/B_{0.01 GRL-519}, p=0.0077; CFP^A/B_{No Drug} vs CFP^A/B_{0.1 GRL-519}, p=0.0003; CFP^A/B_{No Drug} vs CFP^A/B_{1.0 GRL-519}, p=0.0002; CFP^A/B_{0.01 DRV} vs CFP^A/B_{0.01 GRL-519}, p=0.013. Panel A: HIV_WT vs rHIV_WTpro^75/219gag, p=0.53; HIV_WT vs rHIV_WTpro^{12/75/219/309/409gag}, p=0.0080; HIV_WT vs rHIV_WTpro^219/409gag, p=0.22; rHIV_WTpro^75/219gag vs rHIV_WTpro^{12/75/219/309/409gag}, p=0.0065; rHIV_WTpro^75/219gag vs rHIV_WTpro^219/409gag, p=0.15; rHIV_{WT pro}^{12/75/219/309/409gag} vs rHIV_WTpro^219/409gag, p=0.0018. Panel B: HIV_WT vs rHIV_WTpro^75/219gag, p=0.65; HIV_WT vs rHIV_WTpro^{12/75/219/309/409gag}, p<0.0001; HIV_WT vs rHIV_WTpro^219/409gag, p<0.0001;

Figure 3
A. GRL-0519A-bound X-ray structure of HIV-1 protease. The major orientation of the inhibitor is shown. The inhibitor carbon atoms are shown in cyan, water molecules are red spheres, and the hydrogen bonds are indicated by dotted lines. B. Polar interactions of third THF with the protease. The hydrogen bonds are indicated by dotted lines and CH…O interactions by dashed lines.

Scheme 1 — Scheme 1
Synthesis of the Syn-Syn-Syn-tris-THF Ligand 12.

Scheme 2 — Scheme 2
Synthesis of Syn-Anti-Syn-tris-THF alcohol 18

Scheme 3 — Scheme 3
Synthesis of inhibitors 3 and 4.

See this image and copyright information in PMC

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