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Open AccessArticle

Towards an Understanding of the Mode of Action of Human Aromatase Activity for Azoles through Quantum Chemical Descriptors-Based Regression and Structure Activity Relationship Modeling Analysis

1
Laboratory of Environmental Chemistry and Toxicology, Department of Environmental Health Sciences, Istituto di RicercheFarmacologiche “Mario Negri”—IRCCS, Via Mario Negri, 2, 20156 Milano, Italy
2
Jozef Stefan International Postgraduate School, Jamovacesta 39, 1000 Ljubljana, Slovenia
*
Authors to whom correspondence should be addressed.
Academic Editor: Marjan Vračko
Molecules 2020, 25(3), 739; https://doi.org/10.3390/molecules25030739
Received: 20 December 2019 / Revised: 6 February 2020 / Accepted: 6 February 2020 / Published: 8 February 2020
(This article belongs to the Special Issue Integrated QSAR)
Aromatase is an enzyme member of the cytochrome P450 superfamily coded by the CYP19A1 gene. Its main action is the conversion of androgens into estrogens, transforming androstenedione into estrone and testosterone into estradiol. This enzyme is present in several tissues and it has a key role in the maintenance of the balance of androgens and estrogens, and therefore in the regulation of the endocrine system. With regard to chemical safety and human health, azoles, which are used as agrochemicals and pharmaceuticals, are potential endocrine disruptors due to their agonist or antagonist interactions with the human aromatase enzyme. This theoretical study investigated the active agonist and antagonist properties of “chemical classes of azoles” to determine the relationships of azole interaction with CYP19A1, using stereochemical and electronic properties of the molecules through classification and multilinear regression (MLR) modeling. The antagonist activities for the same substituent on diazoles and triazoles vary with its chemical composition and its position and both heterocyclic systems require aromatic substituents. The triazoles require the spherical shape and diazoles have to be in proper proportion of the branching index and the number of ring systems for the inhibition. Considering the electronic aspects, triazole antagonist activity depends on the electrophilicity index that originates from interelectronic exchange interaction (ωHF) and the LUMO energy ( E LUMO PM 7 ), and the diazole antagonist activity originates from the penultimate orbital ( E HOMONL PM 7 ) of diazoles. The regression models for agonist activity show that it is opposed by the static charges but favored by the delocalized charges on the diazoles and thiazoles. This study proposes that the electron penetration of azoles toward heme group decides the binding behavior and stereochemistry requirement for antagonist activity against CYP19A1 enzyme. View Full-Text
Keywords: aromatase CYP19A1 enzyme; agonist; antagonist; quantum-mechanical descriptors; stereochemistry aromatase CYP19A1 enzyme; agonist; antagonist; quantum-mechanical descriptors; stereochemistry
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MDPI and ACS Style

Chayawan, C.; Toma, C.; Benfenati, E.; Caballero Alfonso, A.Y. Towards an Understanding of the Mode of Action of Human Aromatase Activity for Azoles through Quantum Chemical Descriptors-Based Regression and Structure Activity Relationship Modeling Analysis. Molecules 2020, 25, 739.

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