Click chemistry in silico, docking, quantum chemical calculations, and molecular dynamics simulations to identify novel 1,2,4-triazole-based compounds as potential aromatase inhibitors

Abstract

Computational development of novel triazole-based aromatase inhibitors (AIs) was carried out followed by investigation of the possible interaction modes of these compounds with the enzyme and prediction of the binding affinity 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 energies and dissociation constants. At the final stage, structures of the top ranking compounds bound to aromatase were analyzed by molecular dynamic simulations and binding free energy calculations. 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. Six of eight compounds are shown to coordinate the aromatase heme group by the nitrogen–heme–iron interaction typical for triazole-based molecules. At the same time, two compounds form a coordination bond with the heme iron of the enzyme via the lone-pair electrons of their oxygen atoms, which is uncharacteristic for molecules with triazole moieties. All the identified compounds are also involved in 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, Thr-310, Val-370, Met-374, Leu-477, and Ser-478. In addition, most of these compounds form hydrogen bond with Met-374 mimicking the interaction of aromatase with the natural substrate androstenedione, and individual ligands participate in specific π- or T-stacking interactions with the pyrrole rings of the enzyme heme group as well as 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 dissociation constant and binding free energy. Taken together, the data obtained suggest that the identified compounds may present good scaffolds for the development of novel potent drugs against breast cancer.