Structure-Based Design of Potent HIV-1 Protease Inhibitors with Modified P1-Biphenyl Ligands: Synthesis, Biological Evaluation, and Enzyme–Inhibitor X-ray Structural Studies

Ghosh, Arun K.; Yu, Xufen; Osswald, Heather L.; Agniswamy, Johnson; Wang, Yuan Fang; Amano, Masayuki; Weber, Irene T.; Mitsuya, Hiroaki

doi:10.1021/acs.jmedchem.5b00676

Cited by 24 publications

(22 citation statements)

References 38 publications

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“…Inhibitor 4 turned out to be a very potent inhibitor. 13 However, the X-ray structure of 4 -bound HIV-protease showed that the binding mode of the biphenyl ring was different than what we desired. The biphenyl ring rotated away from the S2 site and filled in a hydrophobic channel in the extended S1 subsite.…”

Section: Introductionmentioning

confidence: 68%

Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation

et al. 2016

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A series of potent HIV-1 protease inhibitors with a lipophilic adamantyl P1 ligand have been designed, synthesized and evaluated. We have developed an enantioselective synthesis of adamantane-derived hydroxyethylamine isostere utilizing Sharpless asymmetric epoxidation as the key step. Various inhibitors incorporating P1-adamanylmethyl in combination with P2-ligands such as 3-(R)-THF, 3-(S)-THF, bis-THF and THF-THP were examined. The S1′ pocket was also probed with phenyl and phenylmethyl ligands. Inhibitor 15d, with an isobutyl P1′ ligand and a bis-THF P2 ligand proved to be the most potent of the series. The cLogP value of inhibitor 15d is impoved compared to inhibitor 2 with a phenylmethyl P1-ligand. X-ray structural studies of 15d, 15h and 15i with HIV-1 protease complexes revealed molecular insight into the inhibitor-protein interaction.

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Section: Introductionmentioning

confidence: 68%

Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation

et al. 2016

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“…In addition, the activity decreased when the nitrogen atom of ( R )-piperidine scaffold was methylated, such as 22a vs 24a , 22b vs 24b , 22c vs 24c , and 22d vs 24d . The results might be attributed to both the smaller volume of the P2-ligand which was more suitable for the cavity of S2 Appendix -subsite and the capacity of the exposed nitrogen atom which could form hydrogen bonding interactions with the carbonyl oxygen or amide NHs of Asp30 and Asp29 [ 25 – 28 ].…”

Section: Resultsmentioning

confidence: 99%

Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study

Zhou

Zhu

et al. 2020

PLoS ONE

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A series of potent HIV-1 protease inhibitors, containing diverse piperidine analogues as the P2-ligands, 4-substituted phenylsulfonamides as the P2'-ligands and a hydrophobic cyclopropyl group as the P1'-ligand, were designed, synthesized and evaluated in this work. Among these twenty-four target compounds, many of them exhibited excellent activity against HIV-1 protease with half maximal inhibitory concentration (IC 50) values below 20 nM. Particularly, compound 22a containing a (R)-piperidine-3-carboxamide as the P2-ligand and a 4-methoxylphenylsulfonamide as the P2'-ligand exhibited the most effective inhibitory activity with an IC 50 value of 3.61 nM. More importantly, 22a exhibited activity with inhibition of 42% and 26% against wild-type and Darunavir (DRV)-resistant HIV-1 variants, respectively. Additionally, the molecular docking of 22a with HIV-1 protease provided insight into the ligand-binding properties, which was of great value for further study.

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“…Human immunodeficiency virus-1 (HIV-1) protease (PR) is an enzyme essential for HIV-1 replication [1][2][3][4][5]. Although structure-based drug design has resulted in the development of various PR inhibitors, the long-term effectiveness of the inhibitors is hampered by generation of drug-resistance mutations [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. To understand the mechanism of the drug-resistance, thermodynamics studies of inhibitor interactions with PR and various drug-resistant mutants have been conducted for the past two decades [21][22][23][24][25][26][27][28][29][30][31][32][33].…”

Section: Introductionmentioning

confidence: 99%

An inhibitor-interaction intermediate of HIV-1 protease, revealed by Isothermal Titration Calorimetry and NMR spectroscopy

Khan

Persons

Guerrero

et al. 2018

Preprint

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Some of drug-resistant mutants of HIV-1 protease (PR), such as a clinically-relevant drugresistant PR mutant (Flap+ (I54V) ) containing L10I, G48V, I54V and V82A mutations, produce significant changes in the balance between entropy and enthalpy of the drug-PR interactions, compared to the wild-type (WT) PR. Here, to gain a comprehensive understanding of the entropy-enthalpy compensation effects, we compared nuclear magnetic resonance (NMR), fluorescence spectroscopy and isothermal titration calorimetry (ITC) data of a WT PR with Flap+ (I54V) and related mutants: (1) Flap+ (I54V) ; (2) Flap+ (I54A) which evolves from Flap+ (I54V) in the continued presence of inhibitor yet does not exhibit entropy-enthalpy compensation; and (3) Flap+ (I54) , a control mutant that contains only L10I, G48V and V82A mutations. Our data indicate that WT and Flap+ (I54A) show enthalpy-driven inhibitor-interaction, while Flap+ (I54) and Flap+ (I54V) exhibit entropy-driven inhibitor interaction. Interestingly, Flap+ (I54A) exhibited significantly slower heat flow in the competitive ITC experiment with a strong binder, darunavir, and a weak binder, acetyl-pepstatin, but did not exhibit such slow heat flow in the direct inhibitor-titration experiments. NMR confirmed replacement of the weak binder by the strong binder in a competitive manner. This difference in the heat flow of the competitive binding experiment compared to the direct experiment can only be explained by assuming an inhibitor-bound intermediate pathway. A similar, but attenuated, tendency for slow heat flow was also detected in the competitive experiment with WT. Overall, our data suggests that an inhibitor-bound intermediate affects the entropy-enthalpy compensation of inhibitor-PR interaction.

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Structure-Based Design of Potent HIV-1 Protease Inhibitors with Modified P1-Biphenyl Ligands: Synthesis, Biological Evaluation, and Enzyme–Inhibitor X-ray Structural Studies

Cited by 24 publications

References 38 publications

Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation

Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation

Piperidine scaffold as the novel P2-ligands in cyclopropyl-containing HIV-1 protease inhibitors: Structure-based design, synthesis, biological evaluation and docking study

An inhibitor-interaction intermediate of HIV-1 protease, revealed by Isothermal Titration Calorimetry and NMR spectroscopy

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