Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors

Ekins, Sean; Mankowski, Dayna C.; Hoover, Dennis J.; Lawton, Michael; Treadway, Judith L.; Harwood, H. James

doi:10.1124/dmd.106.013888

Cited by 40 publications

(46 citation statements)

References 59 publications

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“…The pharmacophore for MIC-forming compounds ( Fig. 2A) is similar to previously published pharmacophores for CYP3A4 inhibitors (Ekins et al, 1999a(Ekins et al, , 2003b and autoactivators (Ekins et al, 1999b), indicating that these binding sites may overlap to some extent. Compounds that inactivate but do not form MIC with CYP3A4 may possess all of these features but be too large overall.…”

Section: Discussionsupporting

confidence: 59%

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)

Jones¹,

Ekins²,

Li³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Some mechanism-based inhibitors cause irreversible inhibition by forming a metabolic intermediate complex (MIC) with cytochrome P450. In the present study, 54 molecules (substrates of CYP3A and amine-containing compounds that are not known substrates of CYP3A) were spectrophotometrically assessed for their propensity to cause MIC formation with recombinant CYP3A4 (؉b 5 ). Comparisons of common physicochemical properties showed that mean (؎S.D.) mol. wt. of MIC-forming compounds was significantly greater than mean mol. wt. of non-MIC-forming compounds, 472 (؎173) versus 307 (؎137), respectively. Computational pharmacophores, logistic regression, and recursive partitioning (RP) approaches were applied to predict MIC formation from molecular structure and to generate a quantitative structure activity relationship. A pharmacophore built with SKF-525A (2-diethylaminoethyl 2:2-diphenylvalerate hydrochloride), erythromycin, amprenavir, and norverapamil indicated that four hydrophobic features and a hydrogen bond acceptor were important for these MIC-forming compounds. Two different RP methods using either simple descriptors or 2D augmented atom descriptors indicated that hydrophobic and hydrogen bond acceptor features were required for MIC formation. Both of these RP methods correctly predicted the MIC formation status with CYP3A4 for 10 of 12 literature molecules in an independent test set. Logistic multiple regression and a third classification tree model predicted 11 of 12 molecules correctly. Both models possessed a hydrogen bond acceptor and represent an approach for predicting CYP3A4 MIC formation that can be improved using more data and molecular descriptors. The preliminary pharmacophores provide structural insights that complement those for CYP3A4 inhibitors and substrates.

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Section: Discussionsupporting

confidence: 59%

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)

Jones¹,

Ekins²,

Li³

et al. 2007

Drug Metab Dispos

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“…Additional CYP51 enzymes that exhibit narrow substrate specificities include obtusifoliol-specific Trypanosoma brucei CYP51 and plant CYP51 enzymes, such as Sorghum bicolor CYP51 (36), while the Aspergillus fumigatus CYP51A and CYP51B isoenzymes have a strong preference for eburicol (29). The Trub51 K m for eburicol of 2 M was comparable to the substrate K m values previously obtained for CYP51 enzymes from C. albicans and Saccharomyces cerevisiae (32, 37, 38) but was 5-to 30-fold lower than those determined for CYP51 enzymes from Leishmania infantum, Homo sapiens, Mycosphaerella graminicola, and Malassezia globosa (23,31,36,39). The strict eburicol substrate specificity of Trub51 could not be directly attributable to changes in the primary amino acid sequence of the six substrate recognition sites (28) relative to the primary amino acid sequences of fungal CYP51 enzymes that readily demethylate both eburicol and lanosterol (see Fig.…”

Section: Discussionsupporting

confidence: 56%

The Tetrazole VT-1161 Is a Potent Inhibitor of Trichophyton rubrum through Its Inhibition of T. rubrum CYP51

Warrilow

Parker

Price

et al. 2017

Antimicrob Agents Chemother

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Prior to characterization of antifungal inhibitors that target CYP51, Trichophyton rubrum CYP51 was expressed in Escherichia coli, purified, and characterized. T. rubrum CYP51 bound lanosterol, obtusifoliol, and eburicol with similar affinities (dissociation constant [K d ] values, 22.7, 20.3, and 20.9 M, respectively) but displayed substrate specificity, insofar as only eburicol was demethylated in CYP51 reconstitution assays (turnover number, 1.55 min Ϫ1 ; K m value, 2 M). The investigational agent VT-1161 bound tightly to T. rubrum CYP51 (K d ϭ 242 nM) with an affinity similar to that of clotrimazole, fluconazole, ketoconazole, and voriconazole (K d values, 179, 173, 312, and 304 nM, respectively) and with an affinity lower than that of itraconazole (K d ϭ 53 nM). Determinations of 50% inhibitory concentrations (IC 50 s) using 0.5 M CYP51 showed that VT-1161 was a tight-binding inhibitor of T. rubrum CYP51 activity, yielding an IC 50 of 0.14 M, whereas itraconazole, fluconazole, and ketoconazole had IC 50 s of 0.26, 0.4, and 0.6 M, respectively. When the activity of VT-1161 was tested against 34 clinical isolates, VT-1161 was a potent inhibitor of T. rubrum growth, with MIC 50 , MIC 90 , and geometric mean MIC values of Յ0.03, 0.06, and 0.033 g ml Ϫ1 , respectively. With its selectivity versus human CYP51 and drugmetabolizing cytochrome P450s having already been established, VT-1161 should prove to be safe and effective in combating T. rubrum infections in patients.

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“…CL int,in vitro values of diclofenac, ibuprofen, warfarin, and zaleplon were approximately similar to reported values using cryopreserved hepatocytes (Ekins and Obach, 2000;Nagilla et al, 2006;Stringer et al, 2008), supporting the idea that CL int,in vitro values are similar in fresh hepatocytes and cryopreserved hepatocytes (Naritomi et al, 2003;McGinnity et al, 2004).…”

Section: Discussionsupporting

confidence: 71%

“…It has become possible recently to predict CL and half-life (t 1/2 ) by means of computational approaches and physiologically based modeling (Ekins and Obach, 2000;De Buck et al, 2007;Tabata et al, 2009;Paixão et al, 2010). Accurate prediction of human PK is a key issue for the development of new drugs, because many new drug candidates with diverse chemical structures are metabolized not only by cytochrome P450 (P450) but also by non-P450 enzymes, such as UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT).…”

Section: Introductionmentioning

confidence: 99%

Prediction of In Vivo Hepatic Clearance and Half-Life of Drug Candidates in Human Using Chimeric Mice with Humanized Liver

Sanoh

Horiguchi²,

Sugihara³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Accurate prediction of pharmacokinetics (PK) parameters in humans from animal data is difficult for various reasons, including species differences. However, chimeric mice with humanized liver (PXB mice; urokinase-type plasminogen activator/severe combined immunodeficiency mice repopulated with approximately 80% human hepatocytes) have been developed. The expression levels and metabolic activities of cytochrome P450 (P450) and non-P450 enzymes in the livers of PXB mice are similar to those in humans. In this study, we examined the predictability for human PK parameters from data obtained in PXB mice. Elimination of selected drugs involves multiple metabolic pathways mediated not only by P450 but also by non-P450 enzymes, such as UDP-glucuronosyltransferase, sulfotransferase, and aldehyde oxidase in liver. ). Elimination half-life (t 1/2 ) after intravenous administration also showed a good correlation (r 2 ‫؍‬ 0.886, p ‫؍‬ 1.506 ؋ 10 ؊4) between humans and PXB mice. The rank order of CL and t 1/2 in human could be predicted at least, although it may not be possible to predict absolute values due to rather large prediction errors. Our results indicate that in vitro and in vivo experiments with PXB mice should be useful at least for semiquantitative prediction of the PK characteristics of candidate drugs in humans.

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Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors

Cited by 40 publications

References 59 publications

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)

The Tetrazole VT-1161 Is a Potent Inhibitor of Trichophyton rubrum through Its Inhibition of T. rubrum CYP51

Prediction of In Vivo Hepatic Clearance and Half-Life of Drug Candidates in Human Using Chimeric Mice with Humanized Liver

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Three-Dimensional Quantitative Structure-Activity Relationship Analysis of Human CYP51 Inhibitors

Cited by 40 publications

References 59 publications

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b5)

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b5)

The Tetrazole VT-1161 Is a Potent Inhibitor of Trichophyton rubrum through Its Inhibition of T. rubrum CYP51

Prediction of In Vivo Hepatic Clearance and Half-Life of Drug Candidates in Human Using Chimeric Mice with Humanized Liver

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Resources

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Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)

Computational Approaches That Predict Metabolic Intermediate Complex Formation with CYP3A4 (+b₅)