Albany 2019: 20th Conversation - Abstracts

category image Albany 2019
Conversation 20
June 11-15 2019
Adenine Press (2019)

Computational Design of Novel 1,2,4-Triazole-Based Compounds as Potential Aromatase Inhibitors

In women organism during the fertile phase, estrogen synthesis occurs mainly in the ovaries. However, the intensity of estrogen synthesis in the ovaries decreases in postmenopause associated with about a third of cases of breast cancer. At this phase, estrogens synthesized in the peripheral tissues using the cytochrome P450 enzyme complex, called aromatase. This complex consists of the heme-containing cytochrome P450 (CYP19A1) protein and flavoprotein NADPH-cytochrome P450 reductase. Aromatase that is encoded by a single large gene, CYP19A1, catalyzes conversion of androgens to estrogens and exhibits biological activity in both peripheral target tissues and in the mammary tumor tissues, providing a high level of estrogen concentration. In estrogen-dependent malignant neoplasms, estrogens act as growth factors for tumor development. Therefore, inhibition of aromatase results in a decrease in the level of estrogen in the organism and prevention of the growth and spread of cancer cells.

The third-generation aromatase inhibitors (AIs), which are now used as first-line therapy in the treatment of early- and advanced-stage breast cancer in postmenopausal women, include two categories: the reversible non-steroidal inhibitors anastrozole and letrozole and the steroidal inhibitor exemestane. Although these AIs are currently popular and effective in the treatment of postmenopausal estrogen receptor positive breast cancer, the search for novel drugs still remains necessary to avoid the risk of possible emerging resistances to available drugs as well as to reduce toxicity and undesirable side effects associated with a prolonged use.

In this study, computational development of novel triazole-based AIs was carried out followed by evaluation of their antitumor activity by tools of molecular modeling. In doing so, in silico design of potential AIs candidates fully satisfying the Lipinski's “rule of five” was performed using the concept of click chemistry. Complexes of these drug-like molecules with the enzyme were then simulated by molecular docking and optimized by semiempirical quantum chemical method PM7. To identify the most promising compounds, stability of the PM7-based ligand/aromatase structures was estimated in terms of the values of binding free energy and dissociation constant. As a result, eight hits that specifically interact with the aromatase catalytic site and exhibit the high-affinity ligand binding were selected for the final analysis. All these compounds are shown to coordinate the iron atom of the aromatase heme group and form multiple van der Waals contacts with the critically important residues of the enzyme hydrophobic pocket, such as Arg-115, Ile-133, Phe-134, Trp-224, Тhr-310, Val-370, Met-374, Leu-477, and Ser-478. Six of eight compounds form hydrogen bond with Met-374 mimicking the interaction of aromatase with the natural substrate androstenedione. In addition, individual ligands are also involved in specific π- or T-stacking interactions with the pyrrole rings of the enzyme heme group as well as participate in hydrogen bonding with Thr-310, Leu-372, Leu-477, and Ser-478. The selected AIs candidates show strong attachment to the enzyme active site, in line with the low values of binding free energy and dissociation constant.

Taken together, the data obtained suggest that the identified compounds may present good scaffolds for the development of novel potent drugs against breast cancer. Surely, the properties of these virtual compounds warrant further biological characterization as cellular assays to confirm in vitro their interesting in silico profile.

Alexander M. Andrianova
Grigory I. Nikolaevb
Yuri V. Kornoushenkoa
Sergei A. Usanova

aInstitute of Bioorganic Chemistry
National Academy of Sciences of Belarus
220141 Minsk, Belarus
bUnited Institute of Informatics Problems
National Academy of Sciences of Belarus
220012 Minsk, Belarus

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Email: alexande.andriano@yandex.ru