Kidney Week

Abstract: TH-PO0010

Identification of Novel Compounds Activating the Key Gut Oxalate Transporter SLC26A6 Using a High-Throughput Structure-Based Computational Virtual Screening: Implications for Oxalate-Related Disorders

Session Information

• Mineral Balance: Physiology and Pathophysiology
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Hassan, Hatim A., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Hatim A. Hassan, MD, PhD, FASN

• Wang, Yanzhe, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Yanzhe Wang, MD, PhD

• Islam, Naeyma N., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Naeyma N. Islam, PhD

• Amirkhani Namagerdi, Asadoor A., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Asadoor A. Amirkhani Namagerdi, MD, PhD

• Abdelhalim, Khalid A., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Khalid A. Abdelhalim, PhD

• Coban, Matt, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Matt Coban

• Selvaraj, Manikandan, Mayo Clinic Minnesota, Rochester, Minnesota, United States

Manikandan Selvaraj, PhD

• Weber, Caleb A., Mayo Clinic Minnesota, Rochester, Minnesota, United States

Caleb A. Weber

• Caulfield, Thomas, Digital Ether Computing, Miami, Florida, United States

Thomas Caulfield

Background

Kidney stones (KS) affect ~1 in 5 men and 1 in 11 women. 70-80% of KS are composed of calcium oxalate and even small increases in urine oxalate enhance supersaturation and KS risk. Recurrence rate remains high, emphasizing the need for plasma and urinary oxalate lowering therapies, which can be achieved by enhancing gut oxalate secretion. The gut oxalate transporter SLC26A6 (A6) plays a crucial role in gut oxalate secretion, and our previous findings (JASN, 2017; AJP-Cell Physiol, 2023) support that A6 is potentially druggable.

Methods

To identify small molecule (SM) activators (SMAs) and/or positive allosteric modulators (PAMs) which can directly stimulate A6-mediated gut oxalate secretion, we modeled A6 3D structure and predicted binding site. We applied a high-throughput, structure-based computational virtual screening of >1 billion commercially available compounds (CPs) at the A6 predicted binding site. CPs were prioritized based on predicted binding affinity, drug-like properties, and interaction profiles, leading to identification of 305 high-confidence candidates.

Results

23 of 56 tested CPs stimulated oxalate transport in human intestinal Caco2-BBE (C2) cells by >50% (>100% from 13), with 11 having no effects and 4 with inhibitory effects. DIDS (A6 inhibitor) completely abolished the CPs-induced stimulation, supporting that it is likely A6-mediated. Several CPs produced biphasic concentration-response profiles, with better stimulation at low/intermediate concentrations and reduced potentiation at higher concentration, suggesting concentration-dependent modulation of transporter activity (stimulation in C2 cells by one CP: ~56%, 66%, 90%, 128%, and 77% at 0.01, 0.1, 1, 10, & 100 µM, respectively). Molecular dynamics simulation studies combined with computational mutational analysis reveal unique amino acids (aa) differentiating activators from inhibitors from CPs with no effects, with a single aa identified as a critical residue within A6 that appears necessary for the stimulation.

Conclusion

In conclusion, we identified several A6 SMAs and/or PAMs as well as a critical aa in A6 which appears important for the stimulation. Future studies will focus on further mechanistic studies and in vivo testing for the ultimate development of a novel SM therapeutic for oxalate-related disorders.