Defining the active site of cytochrome P-450: the crystal and molecular structure of an inhibitor, SKF-525A
- 1 July 1987
- journal article
- research article
- Published by Oxford University Press (OUP) in Carcinogenesis: Integrative Cancer Research
- Vol. 8 (7) , 881-887
- https://doi.org/10.1093/carcin/8.7.881
Abstract
The crystal and molecular structure of the cytochrome P-450 inhibitor, SKF-525A [2-(diethy1amino)ethyl 2,2diphenylpentenoate; proadifen hydrochloride] is described. Proadifen hydrochloride crystallized from an ethyl acetate and acetic acid mixture in the space group P2 1 / c with one molecule in the asymmetric unit. Cell constants are a = 18.716(4), b = 8.906(1), c = 14.201(3), β = 109.41(1)°. The structure was solved using directmethods and was refined to an R value of 0.047; weighted R of 0.061 using 3757 reflections. From the crystal and molecular structure, it is seen that SKF-525A has two principal modes of complementary interactions with the enzyme available: polar and non-polar. Polar interactions that principally involve the chloride anion, the quaternary nitrogen atom and the carbonyl oxygen atom. In particular, there are two-strong hydrogen bonds, one between Cl . . . HN, 3.090(1) Å, the other between O2 . . ..H-C111 (one of the ethyl hydrogen atoms) at 3.411(2) Å. The other is thrortgh non-polar interactions involving the phenyl and alkyl groups. Comparisons between proadifen hydrochloride and other inhibitors whose atomic coordinates are available reveal common features which correlate with their function. These include groups to provide necessary intermolecular contacts and bulk, such as a pheyl group and a hydrogen bond acceptor, as well as a tetrahedral atom, which allows for substrate flexibilityThis publication has 14 references indexed in Scilit:
- The role of cholesterol 7α-hydroxylase in the hypobetalipoproteinaemic activity of SKF-525A in ratsBiochemical Pharmacology, 1982
- BETA-DIETHYLAMINOETHYL-2,2-DIPHENYLPENTANOATE (SKF 525-A)-MEDIATED TRANSLOCATION OF UTERINE ESTROGEN-RECEPTOR FROM THE CYTOSOLIC TO THE NUCLEAR COMPARTMENT IN ISOLATED RAT UTERI1982
- Microsomal conversion of SKF 525-A and SKF 8742-ABiochemical Pharmacology, 1980
- The importance of the spin equilibrium in cytochrome P-450 for the reduction rate of the heme ironPublished by Walter de Gruyter GmbH ,1979
- New inhibitors of steroid 11.beta.-hydroxylase. Structure-activity relation studies of metyrapone-like compoundsJournal of Medicinal Chemistry, 1977
- The effects of mepyrapone (SU 4885) and some hypercholesterolaemic drugs on hepatic sterol and fatty acid oxidationBiochemical Pharmacology, 1967
- SPECTRAL STUDIES OF DRUG INTERACTION WITH HEPATIC MICROSOMAL CYTOCHROME1967
- INHIBITION OF DRUG METABOLISM .3. INHIBITION OF HEXOBARBITAL METABOLISM IN INTACT RAT AND IN ISOLATED PERFUSED LIVER BY 2-DIETHYLAMINOETHYL 2,2-DIPHENYLVALERATE HCI (SKF 525-A) AND ITS N-DEETHYLATED DERIVATIVES1966
- INHIBITION OF DRUG METABOLISM .4. INDUCTION OF DRUG METABOLISM BY 2-DIETHYLAMINOETHYL 2,2-DIPHENYLVALERATE HCI (SKF 525-A) AND 2,4-DICHLORO-6-PHENYLPHENOXYETHYLDIETHYLAMINE HBR (LILLY 18947) AND EFFECT OF INDUCTION ON INHIBITORY PROPERTIES OF SKF 525-A TYPE COMPOUNDS1966
- INHIBITORY EFFECTS OF BETA-DIETHYLAMINOETHYL DIPHENYLPROPYLACETATE ON A VARIETY OF DRUG METABOLIC PATHWAYS INVITRO1954