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Novel aromatase inhibitors selection using induced fit docking and extra precision methods: Potential clinical use in
Ranjith Kumavath1, Manan Azad1, Pratap Devarapalli1
1Department of Genomic Science, School of Biological Sciences,Central University of Kerala, Padannakad P.O., Kasaragod-671314, Kerala, India.
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.
Insights
Researchers identified two potential small molecule inhibitors, rubivivaxin and rhodethrin, targeting the aromatase enzyme (CYP19A1) crucial in estrogen production for breast cancer. These compounds show promise for enhancing cancer drug sensitivity.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Computational Biology
Background:
- Aromatase (CYP19A1) is a key enzyme in estrogen biosynthesis, frequently deregulated in breast cancer.
- Estrogen overproduction, mediated by aromatase, drives breast cancer cell proliferation.
- Targeting aromatase with small molecule inhibitors is a strategy to enhance cancer cell drug sensitivity.
Purpose of the Study:
- To identify novel small molecules capable of inhibiting aromatase (CYP19A1) activity.
- To utilize molecular docking studies for screening potential CYP19A1 inhibitors.
- To assess drug-likeness and bioactivity of identified compounds.
Main Methods:
- In silico molecular modeling and docking studies using Schrödinger-Maestro v9.3.
- Protein preparation wizard for CYP19A1 modeling, including optimization of key residues.
- Active site identification using the SiteMap tool and ligand docking via Glide.
- Screening of potential ligands based on Glide score, Lipinski's rule, and bioactivity scoring.
Main Results:
- Two compounds, rubivivaxin and rhodethrin, were identified as potential inhibitors of aromatase (CYP19A1).
- These compounds demonstrated favorable interactions with the CYP19A1 active site.
- Rubivivaxin and rhodethrin satisfied in silico drug-likeness and bioactivity parameters.
Conclusions:
- Rubivivaxin and rhodethrin are promising candidates for aromatase inhibition.
- The identified compounds warrant further in vitro and in vivo investigation for breast cancer therapy.
- In silico approaches are effective for discovering novel small molecule inhibitors against CYP19A1.
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