Abstract
Aromatase (CYP19A1) the key enzyme of estrogen biosynthesis, is often deregulated in breast cancer patients. It catalyzes the conversion of androgen to estrogen, thus responsible for production of estrogen in human body. However, it causes over-production of estrogen which eventually leads to proliferation of breast cancer cells. Identification of new small molecule inhibitors targeted against CYP19A1 therefore, facilitates to increase drug sensitivity of cancer cells. In this scenario, the present study aims to identify new molecules which could block or suppress the activity of aromatase enzyme by molecular docking studies using Schrödinger-Maestro v9.3. In this study we used in silico approach by modeling CYP19A1 protein the strcture was subjected to protein preparation wizard; to add hydrogen and optimize the protonation states of Thr310 and Ser478 and Asp309 residues. Active site of the CYP19A1 protein was identified using SiteMap tool of Scchrodinger package. We further carried out docking studies by means of Glid, with various ligands. Based on glid score, potential ligands were screeened and their interaction with CYP19A1 was identified. The best hits were further screened for Lipinski’s rule for drug-likeliness and bioactivity scoring properties. Thus, we report two rubivivaxin and rhodethrin compounds that have successfully satisfied all in silico parameters, necessitating further in vitro and in vivo studies.
Highlights
Breast cancer is the most prevailing malignancy among females, and the second most common cause of cancer-related deaths in women in the United States [1]
Discovery of novel inhibitors is primarily based on computational techniques, among which Induced Fit Docking (IFD) plays a vital role in understanding the molecular interaction between ligand and the active site of protein
A Comparison of IFD score of drug molecules with AIs suggested that the drug molecules namely troglitazone, toremifene, testolactone, danazol, rubivivaxin and rhodethrin showed fairly potent activity against CYP19A1 with more negative IFD Score value
Summary
Breast cancer is the most prevailing malignancy among females, and the second most common cause of cancer-related deaths in women in the United States [1]. An estimated 235,030 new cases of invasive breast cancer are diagnosed among both males and females in the US during 2014 withan estimated death of 40,430 people [2]. Breast cancer is a complex and heterogeneous diseasewith varying clinical outcomes, disease progression, and responses to specific treatmentsattributed by a wide array of elements ranging from tumorintrinsic genetic factorstoextrinsic tumor micro-environmental factors [3]. The estrogen-bound Estrogen Receptor (ER) complex regulates the transcriptome of breast cancer cells by interaction with different transcription factors.Despite the plethora of physiological and pathophysiological functions of estrogen, a large number of ISSN 0973-2063 (online) 0973-8894 (print)
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