Structure-Based Discovery of Imidazo[4,5‑c]pyridine SARM1
Modulators Showing Paradoxical Activation
Steven K. Albanese, Brittany E. Hopkins, Andrea M. Olland, Alexis Fairman, Nadim Shaikh, Shulu Feng, Mahesh Thakkar, Andreas Verras, Alexey Dementiev, Ward G. Walkup 4th, Christian Atsriku, Harathi D. Srinivas, Wayne Allen, Khuram Ashraf, Pieter H. Bos, Peng Hsiao, Kyle Kroeck, Zhijian Liu, Anu Nagarajan, Christopher T. Szlenk, Mats Svensson, Zachary Lee Johnson, Kanishk Kapilashrami, Stephen Rubino, Andrew Kaplan, and Adam M. Levinson.
Journal of Medicinal Chemistry 2026 69 (8), 9521-9536
DOI: 10.1021/acs.jmedchem.6c00352
Published on April 8, 2026
We are proud to share that the Journal of Medicinal Chemistry recently published an article on Schrödinger’s SARM1 project, to which our Structural Biology team contributed through protein production and crystallography support. Our scientists generated the X-ray co-crystal structure of compound 6 bound to the SARM1 TIR domain (PDB entry: 10RA), a key result that helped guide the SAR optimization of the series.
The article describes the structure-based discovery of a new series of SARM1 inhibitors (Sterile alpha and TIR motif-containing protein 1), an NAD+ hydrolase enzyme implicated in axonal degeneration and various neurological diseases. More specifically, it focuses on base-exchange inhibitors (BEIs) built on an imidazo[4,5-c]pyridine scaffold, identified through an original FEP+ (free-energy perturbation) simulation workflow, which reveal a previously undescribed rotameric state of the W662 residue in the SARM1 catalytic site.
This work provides several methodological contributions transferable to other projects:
– an FEP+ workflow adapted for reactive/covalent inhibitors that form an adduct with a cofactor (here NAD+/ADPR), a notoriously challenging case for physics-based modeling;
– a demonstration that physics-based modeling can effectively guide the discovery of new scaffolds despite significant molecular perturbations;
– an important clinical warning about SARM1 BEIs, which can paradoxically activate neurodegeneration at sub-inhibitory doses — a critical caution for clinical development of this inhibitor class.
Congratulations to Schrödinger and to our Structural Biology team at Novalix.
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