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Fast Three Dimensional Pharmacophore Virtual Screening of New Potent Non-Steroid Aromatase Inhibitors

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Fast Three Dimensional Pharmacophore Virtual Screening of New Potent Non-Steroid Aromatase Inhibitors View metadata, citation and similar papers at core.ac.uk brought to you by CORE J. Med. Chem. 2009, 52, 143–150 143 provided by Estudo Geral Fast Three Dimensional Pharmacophore Virtual Screening of New Potent Non-Steroid Aromatase Inhibitors Marco A. C. Neves,† Teresa C. P. Dinis,‡ Giorgio Colombo,*,§ and M. Luisa Sa´ e Melo*,† Centro de Estudos Farmaceˆuticos, Laborato´rio de Quı´mica Farmaceˆutica, Faculdade de Farma´cia, UniVersidade de Coimbra, 3000-295, Coimbra, Portugal, Centro de Neurocieˆncias, Laborato´rio de Bioquı´mica, Faculdade de Farma´cia, UniVersidade de Coimbra, 3000-295, Coimbra, Portugal, and Istituto di Chimica del Riconoscimento Molecolare, CNR, 20131, Milano, Italy ReceiVed July 28, 2008 Suppression of estrogen biosynthesis by aromatase inhibition is an effective approach for the treatment of hormone sensitive breast cancer. Third generation non-steroid aromatase inhibitors have shown important benefits in recent clinical trials with postmenopausal women. In this study we have developed a new ligand- based strategy combining important pharmacophoric and structural features according to the postulated aromatase binding mode, useful for the virtual screening of new potent non-steroid inhibitors. A small subset of promising drug candidates was identified from the large NCI database, and their antiaromatase activity was assessed on an in vitro biochemical assay with aromatase extracted from human term placenta. New potent aromatase inhibitors were discovered to be active in the low nanomolar range, and a common binding mode was proposed. These results confirm the potential of our methodology for a fast in silico high-throughput screening of potent non-steroid aromatase inhibitors. Introduction built and proved to be valuable in understanding the binding 14-16 Aromatase, a member of the cytochrome P450 superfamily determinants of several classes of inhibitors. The low that catalyzes the final and key step of C19 steroids conversion sequence identity between members of different P450 families to estrogens,1 is a very attractive target for the endocrine may, however, limit their potential in structure-based virtual treatment of breast cancer.2 In this sense, attention has been screenings. focused on the discovery of aromatase inhibitors able to decrease An alternative strategy for the rational design of new the circulating levels of estrogens and therefore control the aromatase inhibitors relies on ligand-based virtual screening that progression of hormone sensitive breast cancer.3 can be developed on the basis of the vast information on strong P450 enzymes are monooxygenases that catalyze a large aromatase inhibitors published in the literature. Pharmacophore- number of reactions involved in drug metabolism and synthesis based approaches have been used for both steroid and non- of steroids and lipids.4 There are more than 7700 different P450 steroid aromatase inhibitors, highlighting important physico- 5 chemical features and guiding the design of new potent sequences identified to date. The design of potent and selective 17-20 inhibitors to a single member of this superfamily represents a compounds. However, to date, only a few attempts to very challenging task. In spite of these hurdles, selective perform virtual screening based on such models have been aromatase inhibitors have been discovered, such as fadrozole performed. Langer and co-workers, for instance, have carried and formestane, a second generation of aromatase inhibitors, out a mixed qualitative and quantitative approach for non-steroid aromatase inhibitors, using the HipHop and HypoRefine algo- or exemestane, letrozole, anastrozole, and vorozole, a third 21 generation of aromatase inhibitors.6 On the basis of their rithms of the Catalyst software. The final pharmacophore Downloaded by PORTUGAL CONSORTIA MASTER on July 1, 2009 inhibition mechanisms, these molecules are divided into two model proposed by this group consisted of one aromatic ring feature, one hydrophobic group, two hydrogen bond acceptors, Published on December 11, 2008 http://pubs.acs.org | doi: 10.1021/jm800945c classes: (1) irreversible steroid inactivators such as formestane or exemestane that bind covalently to the enzyme and (2) non- and one excluded volume sphere. Two possible antiaromatase steroid inhibitors such as letrozole or anastrozole that act as candidates were identified on the basis of this approach, one of reversible competitive inhibitors. the compounds being able to decrease in 68% the activity of Improvements in the rational design of new aromatase the enzyme at 36 µM and the other in 15% at the same inhibitors could be obtained once a high resolution 3D structure concentration. of the enzyme becomes available. However, to date, no X-ray In this study we have used known non-steroid aromatase structure of aromatase has been published in the Protein Data inhibitors to derive and validate a new pharmacophore model Bank, despite recent progress in the 3D determination of for fast in silico screening of antiaromatase compounds. The mammalian and human cytochrome P450 enzymes.7-10 On this model combined information about the common pharmacophore basis, several homology models for aromatase11-13 have been features of azole non-steroid inhibitors, information about their binding to the aromatase active site, steric restrictions and a “druglikeness” filter. The large NCIa compound database was * To whom correspondence should be addressed. For G.C.: phone, (+39)0228500031; fax, (+39)0228901239; e-mail, [email protected]. screened using this methodology, and new potent aromatase For M.L.S.M.: phone, (+351)239859990; fax, (+351)239827126; e-mail, inhibitors were identified. The new compounds have in vitro [email protected]. † Laborato´rio de Quı´mica Farmaceˆutica, Faculdade de Farma´cia, Uni- versidade de Coimbra. a Abbreviations: NCI, National Cancer Institute; HYD, hydrophobic ‡ Laborato´rio de Bioquı´mica, Faculdade de Farma´cia, Universidade de group; HBA, hydrogen bond acceptor; HYP, pharmacophoric hypothesis; Coimbra. Cx-N-HBA, hydrogen bond acceptor from a x-membered nitrogen-contain- § Istituto di Chimica del Riconoscimento Molecolare. ing heterocyclic ring; VS, virtual screening; PSA, polar surface area. 10.1021/jm800945c CCC: $40.75 2009 American Chemical Society Published on Web 12/11/2008 144 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 1 NeVes et al. Figure 2. Common-features (Catalyst/HipHop) pharmacophore model of azole non-steroid aromatase inhibitors. The HYP2 pharmacophoric query had four features: two hydrogen bond acceptors (HBA1 and HBA2, green) and two hydrophobic groups (HYD1 and HYD2, cyan). Figure 1. Training set of azole non-steroid aromatase inhibitors used The training set aromatase inhibitors (anastrozole, red; letrozole, yellow; for the common-features (HipHop) pharmacophore model generation. fadrozole, green; vorozole, blue) are represented as the best fit alignment to the model. activity comparable to that of second and third generation a cyano group (anastrozole, letrozole, and fadrozole) or the N2 antiaromatase agents. Furthermore, the most active molecules atom of a methylbenzotriazole (vorozole), and the hydrophobic were docked on the active site of an aromatase homology features superimpose with phenyl rings of all the molecules 12 model and these results were compared with the pharmacoph- (HYD1, Figure 2), the methyl of the anastrozole, or the ore model. piperidine moiety of the fadrozole (HYD2, Figure 2). Pharmacophore models with a small number of points tend Results and Discussion to be unspecific and return a large number of hits when used to 3D-Pharmacophore Generation. Several non-steroid aro- screen large databases. In particular, hydrophobic and hydrogen matase inhibitors have been used for the treatment of breast bond acceptor features match a large number of chemical cancer in postmenopausal women, with clinical efficacy.2 groups, increasing the number of false positives. Therefore, in Having progressed through a preclinical development and an attempt to increase the specificity of HYP2, the HBA1 feature clinical trials, these compounds are expected to include informa- was substituted with new fragment/function pharmacophoric tion about strong antiaromatase potency and selectivity. In this features: the C5-N-HBA and the C6-N-HBA features (Figure study, we have built a training set with low energy conforma- 3). C5-N-HBA matches hydrogen bond acceptors only if present tions of second and third generation aromatase inhibitors, in certain types of five-membered nitrogen-containing hetero- namely, anastrozole, letrozole, fadrozole, and vorozole (Figure cyclic rings (imidazole, 1,2,4-triazole, 1,2,3-triazole, and tetra- 1) and used these molecules to generate a common-features zole), whereas C6-N-HBA matches acceptors from six- pharmacophore model with the HipHop22 algorithm of the membered nitrogen-containing heterocyclic rings (pyridine, Catalyst software.23 Briefly, the program evaluates chemical pyridazine, pyrimidine, and pyrazine). features common to a set of active compounds and generates Cytochrome P450 enzymes have an inner binding pocket with hypotheses for their activity. These hypotheses are spatial well defined volume accessible from the outside by several dispositions of pharmacophoric points providing the compounds’ channels.25 Therefore, besides the physicochemical properties relative alignment in the binding site of the enzyme. Each point of the inhibitor, molecular shape is expected to be extremely Downloaded by
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