Pharmacophore modeling strategies for the development of novel nonsteroidal inhibitors of human aromatase (CYP19)

Muftuoglu, Yagmur; Mustata, Gabriela

doi:10.1016/j.bmcl.2010.03.113

Cited by 35 publications

(38 citation statements)

References 64 publications

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“…As a result, there is a recognized need for next generation inhibitors [23]. A large number of investigators have invested significant effort in the search for novel structures [24][25][26][27] and mechanisms [28][29][30] that bring about adequate aromatase inhibition, while limiting side effects.…”

Section: Introductionmentioning

confidence: 99%

The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents

Pei

et al. 2011

Breast Cancer Res Treat

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To improve the treatment of breast cancer, there has been a need for alternative aromatase inhibitors (AIs) that bring about adequate aromatase inhibition, while limiting side effects. Since two tamoxifen metabolites have been documented as AIs, we tested a wide range of tamoxifen metabolites on aromatase in order to better understand structural interactions with aromatase and constructed structure-function relationships as a first step toward the development of novel inhibitors. The ability of ten tamoxifen metabolites to inhibit recombinant aromatase (CYP19) was tested using microsomal incubations. The selectivity of the most potent aromatase inhibitor identified, norendoxifen, was characterized by studying its ability to inhibit CYP450 enzymes important in clinical drug-drug interactions, including CYP2B6, 2C9, 2C19, 2D6, and 3A. Computerized molecular docking with the X-ray crystallographic structure of aromatase was used to describe the detailed biochemical interactions involved. The inhibitory potency order of the tested compounds was as follows: norendoxifen ≫ 4,4'-dihydroxy-tamoxifen > endoxifen > N-desmethyl-tamoxifen, N-desmethyl-4'-hydroxy-tamoxifen, tamoxifen-N-oxide, 4'-hydroxy-tamoxifen, N-desmethyl-droloxifene > 4-hydroxy-tamoxifen, tamoxifen. Norendoxifen inhibited recombinant aromatase via a competitive mechanism with a K ( i ) of 35 nM. Norendoxifen inhibited placental aromatase with an IC(50) of 90 nM, while it inhibited human liver CYP2C9 and CYP3A with IC(50) values of 990 and 908 nM, respectively. Inhibition of human liver CYP2C19 by norendoxifen appeared even weaker. No substantial inhibition of CYP2B6 and CYP2D6 by norendoxifen was observed. These data suggest that multiple metabolites of tamoxifen may contribute to its action in the treatment of breast cancer via aromatase inhibition. Most of all, norendoxifen may be able to serve as a potent and selective lead compound in the development of improved therapeutic agents. The range of structures tested in this study and their pharmacologic potencies provide a reasonable pharmacophore upon which to build novel AIs.

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Section: Introductionmentioning

confidence: 99%

The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents

Pei

et al. 2011

Breast Cancer Res Treat

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“…The aromatase enzyme is useful catalyst in the biosynthesis of estrogens from androgens. Inhibition of the aromatase enzyme is responsive to have significant action on the progress and expansion of hormone-dependent breast cancers [24,28].…”

Section: Aromatase Inhibitors (Ais)mentioning

confidence: 99%

A Review of Benzopyran Derivatives in Pharmacotherapy of Breast Cancer

Kumar

Singh

Azizur

et al. 2018

Asian J Pharm Clin Res

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One of the naturally occurring compounds containing oxygen moiety is benzopyran. Depending on its substitution pattern, different biological effects are shown. The benzopyran ring system is present in many natural products (such as genistein, hesperidin, and warfarin) as well as synthetic products. It displays pharmacological properties such as antitumor, anti-HIV, antimicrobials, anti-inflammatory, and anticoagulants. The sufficient literature support and the fact that benzopyran has potential as a pharmacophore particularly as anti-breast cancer, etc, current research seemed pertinent keeping in view the mechanism of anti-breast cancer activity. Therefore, the objective of this review is to focus on important benzopyran analogs with anti-breast cancer activity and highlight their mechanisms of action.

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“…Nevertheless, it is clear that structure-based and ligand-based drug design approaches have a great impact on the discovery of anticancer drugs, and the combination provided by these complementary computational methods are even more valuable. One recent example of how both methods could be integrated in cancer research is the development of a "merged" pharmacophore model for aromatase reported by Muftuoglu and Mustata (Muftuoglu and Mustata 2010) toward the identification of better breast cancer drugs. Excluding cancers of the skin, breast cancer is the most frequently diagnosed cancer in women (2011) and ranks second as a cause of cancer death (after lung cancer).…”

Section: Combined Structure-based and Ligand-based Approachesmentioning

confidence: 99%

“…Aromatase has always been considered the most promising target for the endocrine treatment of breast cancer ) because, by inhibiting the aromatase enzyme, the estrogen production is decreased and the tumor growth stopped or reduced. The recent study reported by Muftuoglu and Mustata (Muftuoglu and Mustata 2010) is the first study aimed to develop a pharmacophore model, based on both ligand and structural information, to screen for new classes of effective AIs. The model developed was generated through a merging of a ligand-based model and a structure-based model.…”

Section: Combined Structure-based and Ligand-based Approachesmentioning

confidence: 99%