The role of substrate lipophilicity in determining type 1 microsomal P450 binding characteristics

Al-Gailany, Kais A.S.; Houston, J. Brian; Bridges, James W.

doi:10.1016/0006-2952(78)90521-x

Cited by 58 publications

(14 citation statements)

References 20 publications

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“…The PGIS lipophilic substrate, PGH # , derived from arachidonic acid by PGHS, would then have ready access to the PGIS active site without even leaving the membrane to contact the polar medium. This is consistent with the results from the studies of the relationship between the ER membrane and the substrate access channel for other P450s using hydrophobic drugs [27,28], and fluorescence energy transfer [29]. Alternative hypotheses can be envisaged, including the possibility of proteinprotein interaction.…”

Section: Discussionsupporting

confidence: 88%

Substrate access channel topology in membrane-bound prostacyclin synthase

Deng¹,

Huang²,

So³

et al. 2002

Biochem. J.

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Results from our molecular-modelling and site-directed-mutagenesis studies of prostaglandin I # synthase (PGIS) have suggested that the large PGIS cytoplasmic domain is anchored to the endoplasmic reticulum (ER) membrane by the N-terminal segment in a way that orients the substrate access channel opening to face the membrane. To test this hypothesis we have explored the accessibility of the PGIS substrate channel opening to site-specific antibodies. The working three-dimensional PGIS model constructed by protein homology modelling was used to predict surface portions near the substrate access channel opening. Two peptides corresponding to the surface immediately near the opening [residues 66-75 (P66-75) and 95-116 (P95-116)], and two other peptides corresponding to the surface about 10-20 A H (1 A H l 0.1 nm) away from the opening [residues 366-382 (P366-382) and 472-482 (P472-482)] were used to prepare sitespecific antibodies. All four antipeptide antibodies specifically recognized the synthetic segments of human PGIS and recombinant PGIS, as shown by binding assays and Western-blot analysis. The site-specific antibodies were used to probe the

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Section: Discussionsupporting

confidence: 88%

Substrate access channel topology in membrane-bound prostacyclin synthase

Deng¹,

Huang²,

So³

et al. 2002

Biochem. J.

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“…Similar equations with a parabolic dependence on the logarithm of the partition coefficients for aspecific monooxigenases were interpreted to mean that metabolic conversion of the substrate has to be preceded by a process of penetration into the micro somes (12), possibly to cytochrome P-450 (21). The linear dependence on l\R M of the esterases in question, however, further supports the previous finding (7) that the enzymes are situated on the surface of the microsomes.…”

Section: Discussionsupporting

confidence: 47%

Structural parameters in the microsomal hydrolysis of 3-acyloxy-l, 4-benzodiazepines and the multiplicity of the esterases involved

Maksay

Tegyey

Simon‐Trompler

et al. 1980

European Journal of Drug Metabolism and Pharmacokinetics

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The biotransformation of several prodrug-type esters of centrally acting 1, 4-benzodiazepines was studied. Their rates of hydrolysis catalyzed by the hepatic microsomal fraction of mice were measured by pH-stat. The heterogeneity of the microsomal esterases was investigated with induction by phenobarbital and with inhibition by DFP. The resulting changes in esterase activity indicated that the phenyl-substituted esters separate from the homogenous sets of oxazepam and lorazepam esters. Regression analysis of the relative hydrolysis rates of the homogenous ester sets revealed a similar dependence on the steric ES the polar sigma* and hydrophobic deltaRM terms of the acyl moiety. The role of the polar term shows that a nucleophilic attack of the acyl moiety determines the hydrolysis. The role of hydrophobicity can be attributed to its interrelation with the steric parameter. The common equations for the aliphatic sters of oxazepam and larazepam suggest the similar nature of the esterases in question and the same catalytic mechanism. Different 3-acetoxy-1, 4-benzodiazepines were also synthetised and their maximal hydrolysis rates were quite different. This excludes the possibility that the deacylation step of the enzymes is rate-determining. Instead, our data suggest that acylation of the microsomal esterases is rate-limiting for the hydrolysis of the aliphatic esters of 3-OH-benzodiazepines.

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“…[4] However, for a typical small molecule in medicinal chemistry the replacement of hydrogen atoms by methyl groups leads to a significant increase in lipophilicity, which in turn may adversely affect its physicochemical and pharmacological properties. [72] Moreover, the gem-dimethyl group can itself become a target of metabolic degradation. [73] The case described for the gem-dimethyl group exemplifies the situation with various other substituents, which, similar to the gemdimethyl group, intrinsically possess high lipophilicity, which is generally undesirable in drug discovery.…”

Section: Analogy Of Oxetanes To Gem-dimethyl Groupsmentioning

confidence: 99%

“…[73] The case described for the gem-dimethyl group exemplifies the situation with various other substituents, which, similar to the gemdimethyl group, intrinsically possess high lipophilicity, which is generally undesirable in drug discovery. [72] Therefore, a stable, compact module with reduced lipophilicity and susceptibility to metabolic attack is desirable. By bridging the two methyl groups of the gem-dimethyl unit with an oxygen atom, the so-formed oxetane fulfills precisely these requirements.…”

Section: Analogy Of Oxetanes To Gem-dimethyl Groupsmentioning

confidence: 99%

Oxetanes as Versatile Elements in Drug Discovery and Synthesis

et al. 2010

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Sizable resources, both financial and human, are invested each year in the development of new pharmaceutical agents. However, despite improved techniques, the new compounds often encounter difficulties in satisfying and overcoming the numerous physicochemical and many pharmacological constraints and hurdles. Oxetanes have been shown to improve key properties when grafted onto molecular scaffolds. Of particular interest are oxetanes that are substituted only in the 3-position, since such units remain achiral and their introduction into a molecular scaffold does not create a new stereocenter. This Minireview gives an overview of the recent advances made in the preparation and use of 3-substituted oxetanes. It also includes a discussion of the site-dependent modifications of various physicochemical and biochemical properties that result from the incorporation of the oxetane unit in molecular architectures.

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The role of substrate lipophilicity in determining type 1 microsomal P450 binding characteristics

Cited by 58 publications

References 20 publications

Substrate access channel topology in membrane-bound prostacyclin synthase

Substrate access channel topology in membrane-bound prostacyclin synthase

Structural parameters in the microsomal hydrolysis of 3-acyloxy-l, 4-benzodiazepines and the multiplicity of the esterases involved

Oxetanes as Versatile Elements in Drug Discovery and Synthesis

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