Structure-Guided Virtual Screening of Candidate Inhibitors Targeting the Na+ Binding Pocket of NBCn1 (SLC4A7) Restricted; Files & ToC

Abstract

The electroneutral sodium-bicarbonate cotransporter NBCn1 (SLC4A7) is an important regulator of intracellular pH and has been implicated in breast cancer progression, making it a potential target for inhibitor discovery. NBCn1 transports coupled Na+ and HCO3- inward across the cell membrane. This inward transport helps maintain an alkaline intracellular environment that supports cancer cell survival and growth. Cancer cells are highly metabolically active and produce substantial CO2, which contributes to acid-base stress and extracellular acidification. Rather than being suppressed by these conditions, cancer cells adapt in ways that support continued growth, proliferation, and metastatic behavior. However, NBCn1 remains difficult to target because it is a dynamic membrane transporter and because few selective small-molecule inhibitors are available. In this study, I used structure-guided virtual screening to identify candidate ligands that may inhibit NBCn1 by interacting with the outward-facing sodium-associated pocket centered on the deposited sodium-binding site Na1301, which is referred to here as the S1 pocket.

All docking was based on the outward-facing human NBCn1 cryo-EM structure 9OVR. The Maybridge HitFinder v13 library was used as the main screening dataset. Ligands were prepared through a standardized workflow, docked to the S1 pocket, and prioritized using docking scores together with post-docking structural criteria related to the Na1301 region. To support confidence in the overall workflow, the same general docking strategy was also evaluated using the DUD-E thrombin benchmark.

The Maybridge screen produced a ranked set of candidate compounds with top 50 docking scores ranging from -10.887 to -10.065 kcal/mol. The highest-ranked compounds were JFD00064, SEW01873, GK01385, JFD00491, and RJC03731. In the external benchmark, the workflow achieved a best redocking root-mean-square deviation (RMSD) of 0.363 Å, a receiver operating characteristic area under the curve (ROC-AUC) of 0.817005, and an enrichment factor at 1% (EF1%) of 8.0, supporting the technical credibility of the screening approach.

Together, these results show that the outward-facing NBCn1 structure can serve as a useful framework for identifying and prioritizing candidate ligands for future follow-up. Although docking does not prove binding or inhibition, the ranked compounds identified here provide a biologically motivated starting point for experimental evaluation of potential NBCn1 inhibitors. 

Table of Contents

This table of contents is under embargo until 28 May 2028

About this Honors Thesis

Rights statement

• Permission granted by the author to include this thesis or dissertation in this repository. All rights reserved by the author. Please contact the author for information regarding the reproduction and use of this thesis or dissertation.

School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, Bioinformatics Biology, Cell Biology, Molecular
Keyword	sodium bicarbonate cotransporter NBCn1 virtual screening
Committee Chair / Thesis Advisor	Choi, Inyeong, Emory University
Committee Members	Deal, Roger, Emory University Fossati, Davide, Emory University Qin, Zhaohui, Emory University

Last modified

Primary PDF

Thumbnail	Title	Date Uploaded	Actions
	File download under embargo until 28 May 2028	2026-04-07 10:59:12 -0400	File download under embargo until 28 May 2028

Supplemental Files

Thumbnail	Title	Date Uploaded	Actions