Binding Structures and Potencies of Oxidosqualene Cyclase Inhibitors with the Homologous Squalene−Hopene Cyclase

Lenhart, Alexander; Reinert, D.J.; Aebi, Johannes D.; Dehmlow, Henrietta; Morand, Olivier; Schulz, Georg E.

doi:10.1021/jm0211218

Cited by 50 publications

(65 citation statements)

References 52 publications

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“…Benzophenone-related compounds have also been found to inhibit squalene cyclase, another enzyme in cholesterol biosynthesis (16). Various benzophenones, including DHBP, have also been identified as the ligands of steroid receptors, thus suggesting the potential of these compounds to mimic steroids (32).…”

Section: Discussionmentioning

confidence: 99%

Small-Molecule Scaffolds for CYP51 Inhibitors Identified by High-Throughput Screening and Defined by X-Ray Crystallography

Podust

Kries

Eddine

et al. 2007

Antimicrob Agents Chemother

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Sterol 14␣-demethylase (CYP51), a major checkpoint in membrane sterol biosynthesis, is a key target for fungal antibiotic therapy. We sought small organic molecules for lead candidate CYP51 inhibitors. The changes in CYP51 spectral properties following ligand binding make CYP51 a convenient target for highthroughput screening technologies. These changes are characteristic of either substrate binding (type I) or inhibitor binding (type II) in the active site. We screened a library of 20,000 organic molecules against Mycobacterium tuberculosis CYP51 (CYP51 Mt ), examined the top type I and type II binding hits for their inhibitory effects on M. tuberculosis in broth culture, and analyzed them spectrally for their ability to discriminate between CYP51 Mt and two reference M. tuberculosis CYP proteins, CYP130 and CYP125. We determined the binding mode for one of the top type II hits, ␣-ethyl-N-4-pyridinyl-benzeneacetamide (EPBA), by solving the X-ray structure of the CYP51 Mt -EPBA complex to a resolution of 1.53 Å. EPBA binds coordinately to the heme iron in the CYP51 Mt active site through a lone pair of nitrogen electrons and also through hydrogen bonds with residues H259 and Y76, which are invariable in the CYP51 family, and hydrophobic interactions in a phylumand/or substrate-specific cavity of CYP51. We also identified a second compound with structural and binding properties similar to those of EPBA, 2-(benzo[d]-2,1,3-thiadiazole-4-sulfonyl)-2-amino-2-phenyl-N-(pyridinyl-4)-acetamide (BSPPA). The congruence between the geometries of EPBA and BSPPA and the CYP51 binding site singles out EPBA and BSPPA as lead candidate CYP51 inhibitors with optimization potential for efficient discrimination between host and pathogen enzymes.In eukaryotic organisms, cytochrome P450 enzymes play important roles in many systems, including the biosynthesis of cholesterol, steroid hormones, and vitamins; the control of cardiovascular physiology and systemic blood pressure; drug metabolism; and chemical toxicology and carcinogenesis (23). With respect to their potential for pharmacological development, eukaryotic P450 enzymes may be divided into two groups, drug targets and drug-metabolizing enzymes. Wellestablished P450 drug targets include (i) the aromatase CYP19, required for the conversion of androgens into estrogens (30) and a key target in the treatment of breast cancer; (ii) sterol 14␣-demethylases (CYP51), required for the biosynthesis of membrane sterols, including cholesterol in animals, ergosterol in fungi, and a variety of C-24-modified sterols in plants and protozoa (2), and a key target in the treatment of diseases caused by infectious microbes; and (iii) other biosynthetic sterol hydroxylases (20). The isoform-specific inhibition of P450 enzymes offers promise for the development of therapeutic, insecticidal, and herbicidal agents (7). High-throughput screening (HTS) libraries of small organic molecules and potential drugs against P450 enzymes may thus be key to selecting high-quality compounds in the lead identificat...

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Section: Discussionmentioning

confidence: 99%

Small-Molecule Scaffolds for CYP51 Inhibitors Identified by High-Throughput Screening and Defined by X-Ray Crystallography

Podust

Kries

Eddine

et al. 2007

Antimicrob Agents Chemother

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“…Inhibitors have been designed considering that the most known effective inhibitors of enzymes belonging to the family of squalene and oxidosqualene cyclases share a structure consisting in two well characterized moieties: a moiety bearing a properly shaped tertiary amino function capable of interacting with a catalytically critical Asp455 residue (human numbering) of the enzyme [4,32], and a moiety shaped so as to productively interact with the aromatic residues of the active site. The latter moiety is an isoprenic structure mimicking the squalene skeleton in azasqualene derivatives [26,33], whereas in other series of inhibitors is an electron-deficient aromatic system [4].…”

Section: Discussionmentioning

confidence: 99%

“…The latter moiety is an isoprenic structure mimicking the squalene skeleton in azasqualene derivatives [26,33], whereas in other series of inhibitors is an electron-deficient aromatic system [4]. Crystallographic studies carried on both squalene-hopene cyclase from Alicyclobacillus acidocaldarious and human OSC provided excellent explanations of the inhibitory properties of different compounds bearing an amino function [4,7,32,33].…”

Section: Discussionmentioning

confidence: 99%

Umbelliferone aminoalkyl derivatives as inhibitors of human oxidosqualene-lanosterol cyclase

Oliaro‐Bosso

Taramino

Viola

et al. 2009

Journal of Enzyme Inhibition and Medicinal Chemistry

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Human and murine lanosterol synthases (EC 5.4.99.7) were studied as targets of a series of umbelliferone aminoalkyl derivatives previously tested as inhibitors of oxidosqualene cyclases from other eukaryotes. Tests were carried out on cell cultures of human keratinocytes and mouse 3T3 fibroblasts incubated with radiolabeled acetate, and on homogenates prepared from yeast cells expressing human lanosterol synthase, incubated with radiolabeled oxidosqualene. In cell cultures of both human keratinocytes and mouse 3T3 fibroblasts, the observed inhibition of cholesterol biosynthesis was selective for oxidosqualene cyclase. The most active compounds bear an allylmethylamino chain in position-7 of the coumarin ring. The inhibition was critically dependent on the position and length of the inhibitor side chain, as well as on the type of aminoalkyl group inserted at the end of the same chain. Molecular docking analyses, carried out to clarify details of inhibitors/enzyme interactions, proved useful to explain the observed differences in inhibitory activities.

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“…7) is an important enzyme in cholesterol biosynthesis as it functioned as catalyst for the conversion of 2, 3 -oxidosqualene to lanosterol, the first precursor for sterols. This enzyme locates the downstream from essential branching steps in the pathway of cholesterol synthesis and not influence the formation of intermediates needed for other biosynthetic pathways such as synthesis of isoprenoids, coenzyme Q 10 etc [3][4][5][6][7][8][9] .…”

Section: Introductionmentioning

confidence: 99%

QSAR Studies of Lanosterol Synthase Inhibitors as Potential Antihypercholesterolemic Compounds

Nair¹,

Pushpa²,

Thomas³

et al. 2017

Orient. J. Chem

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The QSAR analysis provides significant structural insight to help the design of novel antihyper cholesterolemic compounds. 2D-QSAR model for a set of 23 LSS inhibitors that have antihyper cholesterolemic activity was derived. The lanosterol synthase inhibitory activity data and various physicochemical descriptors were preferred as dependent and independent variables respectively. The Multiple Linear Regression (MLR) is taken to choose the best model. Here we have derived two best QSAR models to discuss the structural properties significant for the OSC inhibitory activity. In these models, the following parameters 3D-MoRSE parameter (Mor07e), WHIM parameter (G3e), GETAWAY parameter (R6p + ), Radial Distribution Function parameters (RDF110u and RDF110e) have provided for the LSS inhibitory prediction. This structure activity relationship obtained for the molecule is comparable with the QSAR results and this agreed with the results developed from QSAR studies.

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Binding Structures and Potencies of Oxidosqualene Cyclase Inhibitors with the Homologous Squalene−Hopene Cyclase

Cited by 50 publications

References 52 publications

Small-Molecule Scaffolds for CYP51 Inhibitors Identified by High-Throughput Screening and Defined by X-Ray Crystallography

Small-Molecule Scaffolds for CYP51 Inhibitors Identified by High-Throughput Screening and Defined by X-Ray Crystallography

Umbelliferone aminoalkyl derivatives as inhibitors of human oxidosqualene-lanosterol cyclase

QSAR Studies of Lanosterol Synthase Inhibitors as Potential Antihypercholesterolemic Compounds

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