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

Abstract

IntroductionIt is a known fact that Breast cancer is a known universal disease, with an annual prevalence of 1.3 million cases each year, accounts for more than 23 diseases among all malignancies Breast cancer is more common. In spite of major advances and treatments in its early detection, breast carcinoma still remains a significant reason for morbidity and mortality of women around the world [1]. Breast cancer is the second leading reason behind the death of most females. The most common measure of the treatment of breast cancer is surgery typically followed by adjuvant radiation, chemotherapy, and endocrine therapy, but in a few cases, only medication is given along with radiotherapy [2]. About 70% of breast cancers express mutations in estrogen receptor (ER), while most of the breast cancers demonstrate sensitivity to the inhibition of ER. However, due to unknown facts and reasons, several tumors become unmanageable to ER inhibition during metastatic breast cancer [3].Estrogen receptors are the member of the nuclear receptor family, thus tend to act as a ligand-activated transcription factors. The binding of ligand prompts a conformational change in the receptor, which results in its translocation into the nucleus, thus activates transcription of several target genes [4]. Mutations of Esterogen Receptor (ESR1) affect its ligand-binding domain. ESR1 are a key mechanism in accomplishing endocrine resistance in breast carcinoma therapy. The ordinary mutations occur in ER Ligand binding domain results in mutations of Tyrosine/Serionine/Aspargin 537, Asp 538, Glycine, Glutamine, Leucine 536, Methionine 543, Leucine 544 and Aspartic acid 531 amino acid residues [5]. Hormone therapy is usually accustomed to inhibit estrogen receptor signal or block ER production. It is at first effective within the roughly seventy percent of patients with breast carcinoma, who have ER-positive tumors; however, several Abstract 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 ...

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