Targeting SLC4A4: A Novel Approach in Colorectal Cancer Drug Repurposing
Background: Colorectal cancer (CRC) is a complex and increasingly prevalent malignancy with significant challenges in its treatment and prognosis. This study aims to explore the role of the SLC4A4 transporter as a biomarker in CRC progression and its potential as a therapeutic target, particularly i...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
|
| Series: | Current Issues in Molecular Biology |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1467-3045/47/1/67 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832588744148910080 |
|---|---|
| author | Krunal Pawar Pramodkumar P. Gupta Pooran Singh Solanki Ravi Ranjan Kumar Niraj Shanker L. Kothari |
| author_facet | Krunal Pawar Pramodkumar P. Gupta Pooran Singh Solanki Ravi Ranjan Kumar Niraj Shanker L. Kothari |
| author_sort | Krunal Pawar |
| collection | DOAJ |
| description | Background: Colorectal cancer (CRC) is a complex and increasingly prevalent malignancy with significant challenges in its treatment and prognosis. This study aims to explore the role of the SLC4A4 transporter as a biomarker in CRC progression and its potential as a therapeutic target, particularly in relation to tumor acidity and immune response. Methods: The study utilized computational approaches, including receptor-based virtual screening and high-throughput docking, to identify potential SLC4A4 inhibitors. A model of the human SLC4A4 structure was generated based on CryoEM data (PDB ID 6CAA), and drug candidates from the DrugBank database were evaluated using two computational tools (DrugRep and CB-DOCK2). Results: The study identified the compound (5R)-N-[(1r)-3-(4-hydroxyphenyl)butanoyl]-2-decanamide (DB07991) as the best ligand, demonstrating favorable binding affinity and stability. Molecular dynamics simulations revealed strong protein–ligand interactions with consistent RMSD (~0.25 nm), RMSF (~0.5 nm), compact Rg (4.0–3.9 nm), and stable SASA profiles, indicating that the SLC4A4 structure remains stable upon ligand binding. Conclusions: The findings suggest that DB07991 is a promising drug candidate for further investigation as a therapeutic agent against CRC, particularly for targeting SLC4A4. This study highlights the potential of computational drug repositioning in identifying effective treatments for colorectal cancer. |
| format | Article |
| id | doaj-art-09c74b5c117844d5aba1c5ae7bd5a6c1 |
| institution | Kabale University |
| issn | 1467-3037 1467-3045 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Current Issues in Molecular Biology |
| spelling | doaj-art-09c74b5c117844d5aba1c5ae7bd5a6c12025-01-24T13:27:38ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452025-01-014716710.3390/cimb47010067Targeting SLC4A4: A Novel Approach in Colorectal Cancer Drug RepurposingKrunal Pawar0Pramodkumar P. Gupta1Pooran Singh Solanki2Ravi Ranjan Kumar Niraj3Shanker L. Kothari4Amity Institute of Biotechnology, Amity University Rajasthan, SP-1, Kant Kalwar, RIICO Industrial Area, NH-11C, Jaipur 303002, Rajasthan, IndiaSchool of Biotechnology and Bioinformatics, D Y Patil Deemed to be University, Plot 50, Sector 15, CBD Belapur, Navi Mumbai 400614, Maharashtra, IndiaBioinformatics Center, Birla Institute of Scientific Research, Jaipur 302001, Rajasthan, IndiaAmity Institute of Biotechnology, Amity University Rajasthan, SP-1, Kant Kalwar, RIICO Industrial Area, NH-11C, Jaipur 303002, Rajasthan, IndiaAmity Institute of Biotechnology, Amity University Rajasthan, SP-1, Kant Kalwar, RIICO Industrial Area, NH-11C, Jaipur 303002, Rajasthan, IndiaBackground: Colorectal cancer (CRC) is a complex and increasingly prevalent malignancy with significant challenges in its treatment and prognosis. This study aims to explore the role of the SLC4A4 transporter as a biomarker in CRC progression and its potential as a therapeutic target, particularly in relation to tumor acidity and immune response. Methods: The study utilized computational approaches, including receptor-based virtual screening and high-throughput docking, to identify potential SLC4A4 inhibitors. A model of the human SLC4A4 structure was generated based on CryoEM data (PDB ID 6CAA), and drug candidates from the DrugBank database were evaluated using two computational tools (DrugRep and CB-DOCK2). Results: The study identified the compound (5R)-N-[(1r)-3-(4-hydroxyphenyl)butanoyl]-2-decanamide (DB07991) as the best ligand, demonstrating favorable binding affinity and stability. Molecular dynamics simulations revealed strong protein–ligand interactions with consistent RMSD (~0.25 nm), RMSF (~0.5 nm), compact Rg (4.0–3.9 nm), and stable SASA profiles, indicating that the SLC4A4 structure remains stable upon ligand binding. Conclusions: The findings suggest that DB07991 is a promising drug candidate for further investigation as a therapeutic agent against CRC, particularly for targeting SLC4A4. This study highlights the potential of computational drug repositioning in identifying effective treatments for colorectal cancer.https://www.mdpi.com/1467-3045/47/1/67colorectal cancerSLC4A4drug designmolecular dockingmolecular modeling |
| spellingShingle | Krunal Pawar Pramodkumar P. Gupta Pooran Singh Solanki Ravi Ranjan Kumar Niraj Shanker L. Kothari Targeting SLC4A4: A Novel Approach in Colorectal Cancer Drug Repurposing Current Issues in Molecular Biology colorectal cancer SLC4A4 drug design molecular docking molecular modeling |
| title | Targeting SLC4A4: A Novel Approach in Colorectal Cancer Drug Repurposing |
| title_full | Targeting SLC4A4: A Novel Approach in Colorectal Cancer Drug Repurposing |
| title_fullStr | Targeting SLC4A4: A Novel Approach in Colorectal Cancer Drug Repurposing |
| title_full_unstemmed | Targeting SLC4A4: A Novel Approach in Colorectal Cancer Drug Repurposing |
| title_short | Targeting SLC4A4: A Novel Approach in Colorectal Cancer Drug Repurposing |
| title_sort | targeting slc4a4 a novel approach in colorectal cancer drug repurposing |
| topic | colorectal cancer SLC4A4 drug design molecular docking molecular modeling |
| url | https://www.mdpi.com/1467-3045/47/1/67 |
| work_keys_str_mv | AT krunalpawar targetingslc4a4anovelapproachincolorectalcancerdrugrepurposing AT pramodkumarpgupta targetingslc4a4anovelapproachincolorectalcancerdrugrepurposing AT pooransinghsolanki targetingslc4a4anovelapproachincolorectalcancerdrugrepurposing AT raviranjankumarniraj targetingslc4a4anovelapproachincolorectalcancerdrugrepurposing AT shankerlkothari targetingslc4a4anovelapproachincolorectalcancerdrugrepurposing |