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Structure-Based Pharmacophore Modeling, Virtual Screening and Molecular docking for the Treatment of ESR1 Mutations in Breast Cancer

Anum Munir, Shumaila Azam, Azhar Mehmood, Zanib Khan, Arshad Mehmood and Sahar Fazal

Background: Mutations of Estrogen receptors 1 affect its ligand-binding domain and results in the formation of breast cancer. Breast cancer is a known universal disease and the second leading reason behind the death of most females. About 70% of breast cancers express the estrogen receptor. This study was undertaken to realize perceptions into molecular mechanisms and structural necessities that are crucial for potential inhibition of ESR1.

Methods: In this research ESR1 proteins were selected and pharmacophore models were generated, virtual screening was done to obtain hit compounds against reference shared feature pharmacophore, the hit compounds were docked with ESR1 proteins.

Results: The pharmacophore displayed three main features Hydrogen bond acceptor, Hydrogen bond donor and aromatic rings. 10 hit compounds were obtained by virtual screening; compounds were further sorted for Lipinski rule of five before docking. Compounds that fulfill all properties of Lipinski rule of five were docked with proteins, 3 compounds demonstrated ideal docking results. They fit appropriately in the pocket of proteins which demonstrated the soundness and stability of ligand compounds.

Conclusion: It is suggested that these three compounds can be used in the treatment of ESR1 mutations in breast cancer and novel compounds can be designed on the basis of shared feature pharmacophore model for the treatment of ESR1 mutations in breast cancer.