Quantitative structure-activity relationships (QSARs) for inhibitors and substrates of CYP2B enzymes: importance of compound lipophilicity in explanation of potency differences

Lewis, David F.; Ito, Yuko; Lake, Brian G.

doi:10.3109/14756360903514149

Cited by 19 publications

(32 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, several computational approaches have sought to predict potential CYP2B6 substrates based on the structural characteristics of known substrates. [16a–e] Each of these computational approaches determined that lipophilicity, molecular size, and molecular shape were important considerations for predicting CYP2B6 substrates. Compared to EFV, whose theoretical log P is estimated to be 3.68, 1 – 5 have similar log P values ranging from 3–4.…”

Section: Discussionmentioning

confidence: 99%

Single Heteroatom Substitutions in the Efavirenz Oxazinone Ring Impact Metabolism by CYP2B6

Cox

Bumpus

2016

ChemMedChem

View full text Add to dashboard Cite

Previously, we observed that the oxazinone ring is important for CYP2B6 activity toward efavirenz ((4S)-6-Chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one), a CYP2B6 substrate used to treat HIV. Here, to further understand the structural characteristics of efavirenz that render it a CYP2B6 substrate, we test the importance of each heteroatom of the oxazinone ring. We assembled a panel of five analogues: 6-Chloro-4-(2-cyclopropylethynyl)-1,4-dihydro-2-methyl-4-(trifluoromethyl)-2H-3,1-benzoxazine (1), (4S)-6-Chloro-4-[(1E)-2-cyclopropylethenyl]-3,4-dihydro-4-(trifluoromethyl)-,2(1H)-quinazolinone (2), (4S)-6-Chloro-4-(2-cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (3), 6-Chloro-4-(cyclopropylethynyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinolinone (4), and 6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-4H-benzo[d][1,3]dioxin-2-one (5). Metabolism of 1–5 was investigated using human liver microsomes, individual P450s, and mass spectrometry or UV absorbance detection. Steady-state analysis of CYP2B6 metabolism of 1–5 showed KM values ranging from 0.3 to 3.9 fold different than observed for efavirenz (KM of 3.6 ± 1.7 μM). The lowest KM values approximating 1 μM, were observed for metabolism of 1, while the largest KM, 14 ± 6.4 μM, was found for 4. Our work reveals that analogues with heteroatom changes in the oxazinone ring are still CYP2B6 substrates, though the changes KM suggest altered substrate binding.

show abstract

Section: Discussionmentioning

confidence: 99%

Single Heteroatom Substitutions in the Efavirenz Oxazinone Ring Impact Metabolism by CYP2B6

Cox

Bumpus

2016

ChemMedChem

View full text Add to dashboard Cite

show abstract

“…The CYP2B subfamily enzymes are versatile catalysts with a broad range of substrates, preferring angular, medium-sized neutral or basic compounds [11]. Compared with several other CYP subfamilies, the CYP2B subfamily exhibits a relatively low degree of catalytic preservation across mammalian species, providing an excellent model system for structure-function analysis [12, 13].…”

Section: Introductionmentioning

confidence: 99%

Functional importance of a peripheral pocket in mammalian cytochrome P450 2B enzymes

Jang

Liu

Lee

et al. 2015

Archives of Biochemistry and Biophysics

View full text Add to dashboard Cite

The functional importance of a peripheral pocket found in previously published X-ray crystal structures of CYP2B4 and CYP2B6 was probed using a biophysical approach. Introduction of tryptophan within the pocket of CYP2B4 at F202 or I241 leads to marked impairment of 7-ethoxy-4-(trifluoromethyl)coumarin (7-EFC) or 7-benzyloxyresorufin O-dealkylation efficiency; a similar substitution at F195, near the surface access to the pocket, does not affect these activities. The analogous CYP2B6 F202W mutant is inactive in the 7-EFC O-dealkylation assay. The stoichiometry of 7-EFC deethylation suggested that the decreased activity of F202W and I241W in CYP2B4 and lack of activity of F202W in CYP2B6 coincided with a sharp increase in the flux of reducing equivalents through the oxidase shunt to produce excess water. The results indicate that the chemical identity of residues within this peripheral pocket, but not at the mouth of the pocket, is important in substrate turnover and redox coupling, likely through effects on active site topology.

show abstract

“…The LOGP quadratic term has been successfully used before to explain the inhibitory activity of several compounds (barbiturates, alkylbenzimidazoles, aliphatic primary amines, etc.) and their selectivity towards P450 isoforms [30]. On the other hand, the electronic character of sulfonamide derivatives and its correlation with its inhibitory activity over the acetylcholinesterase protein has been properly studied by using quantum chemical descriptors, such as HOMO, LUMO, dipole moment, etc.…”

Section: Molecules Preparationmentioning

confidence: 99%

In silico receptor-based drug design of X,Y-benzenesulfonamide derivatives as selective COX-2 inhibitors

Pérez

Sarabia

Villanueva-García

et al. 2016

Comptes Rendus. Chimie

View full text Add to dashboard Cite

a b s t r a c tCOX-2 is a widely studied biological target, since its activity is directly related to the inflammation response. The design of COX-2 selective inhibitors is an ongoing topic in drug design. We performed a quantitative structureeactivity relationship and docking studies over a series of benzenesulfonamide derivatives on their inhibition towards COX-1 and COX-2, in order to rationalize their selectivity towards COX-2. Constitutional, topological and molecular property descriptors for the QSAR models and molecular docking calculations were employed. The mathematical model highlighted that lipophilic character and size are the most important features for COX-2 inhibition by benzenesulfonamides. A second QSAR model revealed that the dipole moment, the number of hydrogen bond donors and lipophilicity descriptors of benzenesulfonamides are crucial for their binding to COX-1. Moreover, artificial neural networks were employed to improve the prediction power of the COX-1 inhibition QSAR model. In this sense, we proposed new selective potential inhibitors by introducing different halogens into the benzenesulfonamide scaffold, improving their interactions with key residues of COX-2.

show abstract

Quantitative structure-activity relationships (QSARs) for inhibitors and substrates of CYP2B enzymes: importance of compound lipophilicity in explanation of potency differences

Cited by 19 publications

References 26 publications

Single Heteroatom Substitutions in the Efavirenz Oxazinone Ring Impact Metabolism by CYP2B6

Single Heteroatom Substitutions in the Efavirenz Oxazinone Ring Impact Metabolism by CYP2B6

Functional importance of a peripheral pocket in mammalian cytochrome P450 2B enzymes

In silico receptor-based drug design of X,Y-benzenesulfonamide derivatives as selective COX-2 inhibitors

Contact Info

Product

Resources

About