Work

Discovery of MA48, a Small Molecule Inhibitor of CAPON (NOS1AP)-NOS1 Protein-Protein Interaction

Year: 2026

Type: preprint

Abstract: CAPON (also known as NOS1AP) is an adaptor protein of neuronal nitric oxide synthase (nNOS) that has been implicated in the progression of multiple neurodegenerative diseases, making it an attractive but largely unexplored therapeutic target. To identify small molecule CAPON modulators, we screened a library of 10,000 compounds for CAPON binding using affinity selection-mass spectrometry (AS-MS), which led to the identification of compound MA48 as a potential CAPON binder. Subsequent biophysical validation using microscale thermophoresis (MST) confirmed direct binding, with MA48 exhibiting a dissociation constant (Kd) of 11.9 μM. Structure-activity relationship (SAR) analysis combined with molecular docking was performed to elucidate key pharmacophoric features underlying the MA48/CAPON interaction. To determine whether MA48 disrupts the CAPON-nNOS interaction in a cellular context, we conducted a NanoBRET assay, which demonstrated that MA48 significantly inhibited this interaction in living cells. Collectively, these findings suggest that MA48 represents the first reported small molecule inhibitor of CAPON and provides a foundation for further development of CAPON-targeted therapeutics.

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.64898/2026.02.21.707155

Authors: Ashraf N. Abdo, Hossam Nada, Sungwoo Cho, Moustafa Gabr

Institution: Weill Cornell Medicine

Language: English

Topic: Computational Drug Discovery Methods

Subfield: Computational Theory and Mathematics

Field: Computer Science

Domain: Physical Sciences

SDG: Good health and well-being

Open Access status: green

Funder: National Institute on Aging