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Virtual Screening and Binding Analysis of Potential CD58 Inhibitors in Colorectal Cancer (CRC)
Rong Guo1, Jiangnan Yu2, Zhikun Guo2
1Computational Biology, Bioinformatics and Genomics Program, Department of Biological Sciences, University of Maryland, College Park, MD 20742, USA.
Abstract:
Human cell surface receptor CD58, also known as lymphocyte function-associated antigen 3 (LFA-3), plays a critical role in the early stages of immune response through interacting with CD2. Recent research identified CD58 as a surface marker of colorectal cancer (CRC), which can upregulate the Wnt pathway and promote self-renewal of colorectal tumor-initiating cells (CT-ICs) by degradation of Dickkopf 3. In addition, it was also shown that knockdown of CD58 significantly impaired tumor growth. In this study, we developed a structure-based virtual screening pipeline using Autodock Vina and binding analysis and identified a group of small molecular compounds having the potential to bind with CD58. Five of them significantly inhibited the growth of the SW620 cell line in the following in vitro studies. Their proposed binding models were further verified by molecular dynamics (MD) simulations, and some pharmaceutically relevant chemical and physical properties were predicted. The hits described in this work may be considered interesting leads or structures for the development of new and more efficient CD58 inhibitors.
Insights
Researchers identified small molecules that inhibit CD58, a marker on colorectal cancer cells. These compounds show potential for developing new colorectal cancer (CRC) therapies by targeting tumor-initiating cells.
Area of Science:
- Immunology
- Oncology
- Computational Chemistry
Background:
- CD58 (lymphocyte function-associated antigen 3) is a human cell surface receptor crucial for immune responses.
- CD58 is identified as a colorectal cancer (CRC) surface marker, promoting tumor-initiating cell self-renewal via Wnt pathway activation.
- CD58 knockdown impairs colorectal tumor growth, suggesting it as a therapeutic target.
Purpose of the Study:
- To identify small molecular inhibitors of CD58 using structure-based virtual screening.
- To evaluate the efficacy of identified compounds against colorectal cancer cells.
- To validate binding interactions and predict properties of potential CD58 inhibitors.
Main Methods:
- Structure-based virtual screening utilizing Autodock Vina.
- In vitro studies on SW620 colorectal cancer cell line.
- Molecular dynamics (MD) simulations for binding model verification.
- Prediction of pharmaceutically relevant chemical and physical properties.
Main Results:
- A virtual screening pipeline identified compounds with potential to bind CD58.
- Five compounds significantly inhibited the growth of the SW620 cell line.
- MD simulations supported the proposed binding models of the identified compounds.
Conclusions:
- The identified small molecules represent potential lead structures for novel CD58 inhibitors.
- These compounds may offer a new therapeutic strategy for colorectal cancer by targeting CD58.
- Further development of these hits could lead to more efficient CD58-based CRC treatments.
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