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Structure-based elucidation of thiazine inhibitors targeting estrogen receptors alpha: pharmacophore modeling,
M S Sanjeev1, Bhim Singh1, Kailash Jangid1
1Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Ghudda, Bathinda, Pb, 151401, India.
Abstract:
Breast cancer (BC) is considered a highly prevalent cancer among women, with estrogen receptor alpha (ERα) playing a pivotal role in tumor growth and development. Even with existing medications such as tamoxifen, the rising resistance underscores the vital demand for novel ER-positive inhibitors. The present work focuses on identifying a thiazine derivative targeting ERα via pharmacophore model-based drug design. A ligand database of 62 bioactive thiazine derivatives in the MCF-7 cell line was generated and validated using the pharmacophore model (AHRRR_1). An additional 95,296 thiazine derivatives were downloaded and screened against the developed pharmacophore model. 10 HITs were identified via high-throughput virtual screening, standard precision, and extra precision molecular docking with the ERα protein (Protein Data Bank ID: 4XI3). Hence, HIT1 was selected as a potential lead candidate following analysis of the pharmacokinetic profile and binding free energies, as it meets the criteria and has a higher docking score than the reference drug tamoxifen. Beyond this, the stability and structural compactness of the HIT1 were confirmed by a 200 ns molecular dynamics simulation. Subsequently, a Density Functional Theory assessment highlighted the drug-likeness and reactivity of the HIT relative to tamoxifen. Collectively, this research developed a promising lead molecule (HIT1) as a therapeutic approach for ER-positive breast cancer.
Insights
Researchers identified a novel thiazine derivative, HIT1, as a promising therapeutic candidate for estrogen receptor-positive breast cancer. This new compound shows potential to overcome resistance to existing treatments like tamoxifen.
Area of Science:
- Medicinal Chemistry
- Computational Drug Design
- Oncology
Background:
- Breast cancer (BC) is a prevalent cancer in women, with estrogen receptor alpha (ERα) crucial for tumor progression.
- Existing treatments like tamoxifen face challenges due to rising drug resistance, necessitating novel ERα inhibitors.
Purpose of the Study:
- To identify a novel thiazine derivative targeting ERα using pharmacophore model-based drug design.
- To develop a potential therapeutic agent for ER-positive breast cancer.
Main Methods:
- Generated and validated a pharmacophore model (AHRRR_1) using a database of 62 thiazine derivatives.
- Screened 95,296 additional thiazine derivatives against the model, followed by molecular docking with ERα (PDB ID: 4XI3).
- Assessed pharmacokinetic profiles, binding free energies, molecular dynamics, and Density Functional Theory (DFT) for lead candidates.
Main Results:
- Identified 10 potential hits (HITs) through virtual screening and molecular docking.
- Selected HIT1 as a lead candidate due to its superior docking score compared to tamoxifen and favorable pharmacokinetic profile.
- Confirmed HIT1's stability, structural compactness, drug-likeness, and reactivity through molecular dynamics and DFT analyses.
Conclusions:
- HIT1 emerged as a promising lead molecule for the treatment of ER-positive breast cancer.
- The developed thiazine derivative demonstrates potential as a therapeutic approach to overcome tamoxifen resistance.
