Design of Novel Letrozole Analogues Targeting Aromatase for Breast Cancer: Molecular Docking, Molecular Dynamics, and Theoretical Studies on Gold Nanoparticles

The use of aromatase inhibitors is an established therapy for estrogen-dependent breast cancer in postmenopausal women. However, the only commercially available aromatase inhibitor, letrozole, is not highly selective; in addition to aromatase, it has an affinity for binding to desmolase, an enzyme involved in steroidogenesis, which explains the main side effects. Therefore, we designed new compounds based on the structure of letrozole. More than five thousand compounds were constructed based on the letrozole structure. Then, these compounds were screened for their binding ability toward the target protein, aromatase. Quantum docking, Glide docking, and ADME studies showed 14 new molecules with docking scores of ≤−7 kcal/mol, compared to the docking score of −4.109 kcal/mol of the reference, letrozole. Moreover, molecular dynamics (MD) and post-MD MM-GBSA calculations were calculated for the top three compounds, and the results supported in their interaction’s stability. Finally, the density-functional theory (DFT) study applied to the top compound to study the interaction with gold nanoparticles revealed the most stable position for the interaction with the gold nanoparticles. The results of this study confirmed that these newly designed compounds could be useful starting points for lead optimization. Further in vitro and in vivo studies are recommended for these compounds to verify these promising results experimentally.