Structural analysis, solvent effects and intramolecular interactions in rilpivirine: A new non-nucleoside reverse transcriptase inhibitor for HIV treatment

Mirhaji, Elnaz; Yoosefian, Mehdi

doi:10.1016/j.molliq.2017.09.050

Cited by 16 publications

(2 citation statements)

References 24 publications

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“…(2) The cyanovinyl group enhanced the interactions with Y181, Y188, F227, and W229 in the modified hydrophobic tunnel . (3) The NH linker connecting the central pyridine ring and the cyano-phenyl ring, and the nitrogen of the pyrimidine formed hydrogen bonds with the backbone of K101. , The distance between the 6-chloride substituent of compound 12d and E138/K138 was very short (Figure A,D,G). Compound 12n , with a 6-nitro group, formed an additional water-mediated hydrogen bond with the carbonyl of E138 (Figure B).…”

Section: Resultsmentioning

confidence: 99%

Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles

Han

Sang

et al. 2019

ACS Infect. Dis.

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Molecular hybridization is a powerful strategy in drug discovery. A series of novel diarylbenzopyrimidine (DABP) analogues were developed by the hybridization of FDA-approved drugs etravirine (ETR) and efavirenz (EFV) as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Substituent modifications resulted in the identification of new DABPs with the combination of the strengths of the two drugs, especially compound 12d, which showed promising activity toward the EFV-resistant K103N mutant. 12d also had a favorable pharmacokinetic (PK) profile with liver microsome clearances of 14.4 μL/min/mg (human) and 33.2 μL/min/mg (rat) and an oral bioavailability of 15.5% in rat. However, its activity against the E138K mutant was still unsatisfactory; E138K is the most prevalent NNRTI resistance-associated mutant in ETR treatment. Further optimizations resulted in a highly potent compound (12z) with no substituents on the phenyl ring and a 2-methyl-6-nitro substitution pattern on the 4-cyanovinyl-2,6-disubstitued phenyl motif. The antiviral activity of this compound was much higher than those of ETR and EFV against the WT, E138K, and K103N variants (EC50 = 3.4, 4.3, and 3.6 nM, respectively), and the cytotoxicity was decreased while the selectivity index (SI) was increased. In particular, this compound exhibited acceptable intrinsic liver microsome stability (human, 34.5 μL/min/mg; rat, 33.2 μL/min/mg) and maintained the good PK profile of its parent compound EFV and showed an oral bioavailability of 16.5% in rat. Molecular docking and structure–activity relationship (SAR) analysis provided further insights into the binding of the DABPs with HIV-1 reverse transcriptase and provided a deeper understanding of the key structural features responsible for their interactions.

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Section: Resultsmentioning

confidence: 99%

Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles

Han

Sang

et al. 2019

ACS Infect. Dis.

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“…To improve the adsorption feature, SWCNTs can be functionalized through doping, decorating or defecting with impurity atoms sensor. [15][16][17] The shi in Fermi level with dopant metal can modify the reactivity and the electronic properties of SWCNT. 18 Because of the hydrophobic surface of pristine SWCNT, functionalized nanomaterial could be a good candidate as a nanobiosensor because of the biocompatibility and aqueous solubility.…”

Section: Introductionmentioning

confidence: 99%

Ultra-low concentration protein detection based on phenylalanine–Pd/SWCNT as a high sensitivity nanoreceptor

et al. 2020

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Density functional theory study towards investigating the adsorption properties of the γ-Fe2O3 nanoparticles as a nanocarrier for delivery of Flutamide anticancer drug

et al. 2019

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Structural analysis, solvent effects and intramolecular interactions in rilpivirine: A new non-nucleoside reverse transcriptase inhibitor for HIV treatment

Cited by 16 publications

References 24 publications

Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles

Molecular Hybridization-Inspired Optimization of Diarylbenzopyrimidines as HIV-1 Nonnucleoside Reverse Transcriptase Inhibitors with Improved Activity against K103N and E138K Mutants and Pharmacokinetic Profiles

Ultra-low concentration protein detection based on phenylalanine–Pd/SWCNT as a high sensitivity nanoreceptor

Density functional theory study towards investigating the adsorption properties of the γ-Fe2O3 nanoparticles as a nanocarrier for delivery of Flutamide anticancer drug

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