Modulation of aromatase by natural compounds—A pharmacophore guided molecular modelling simulations

Abstract

Abstract Globally, breast cancer is one of the primary reasons of death noticed in women. Despite continuous efforts to formulate effective treatments, search to identify promising therapeutics is underway. Consequently, a drug with low toxicity, high efficacy, and which can escape resistance mechanism is in a high demand. Natural compounds are bestowed with several medicinal properties demonstrating low toxicity. Therefore, the current research focuses on the use of several plant- derived chemical compounds against aromatase, a validated drug target for breast cancer. Correspondingly, employing the known inhibitors, a 3D QSAR pharmacophore model was generated and was subsequently validated. Using the three-featured pharmacophore as the 3D query, the alkaloids, flavonoids, coumarins and the AfroDB were scrupulously examined to retrieve the compounds with inhibitory activities complemented by the pharmacophore model. The obtained compounds were subjected to molecular docking studies executed employing the Cdocker accessible on discovery studio v4.5. The resultant ideal poses from the largest cluster conferred with key reside interactions and higher dock scores than the reference and the Food and Drug Administration (FDA) approved drugs were escalated to molecular dynamics simulation studies conducted employing GROMACS v5.0.6 for 30\u202fns. Correspondingly, the Hits (ZINC95486358, ZINC95486354, and ZINC90711737) have displayed stable root mean square deviations, coupled by appropriate positioning at the active site displaying greater number of hydrogen bonds. Moreover, the Hits (ZINC95486358, ZINC95486354, and ZINC90711737) were noticed to anchor with various key residues essential for clamping the ligand at the binding pocket. Therefore, these findings guide us to determine that the identified Hits can act effectively against breast cancer, thereby increasing the life expectancy. Furthermore, they can assist as scaffolds for designing novel drugs that aid in curing the cancer.