Optimization of Small Molecule Inhibitors against SARM1
QM/MM calculations
Background
• The binding pocket is created by multiple TIRs domains, with the primary binding site located between one TIR domain in the asymmetric unit and the opposite end of a symmetrically oriented TIR.
• For each screening, compounds were aligned by superimposing the ADPR portion of NAD with the ADPR portion of the reference-ADPR adduct.
• Given the crowded patent space, it is essential to filter out non-patentable compounds at an early stage.
Goal: Design potential SARM1 inhibitors that form adducts to provide neuroprotection in nerve injury and disease.
Approach
• Molecules were generated by replacing core structures of reference compounds from an internal fragment library (~1.44 million compounds). A comprehensive virtual screening of the target-focused library was conducted using Uni-QSAR,Uni-Docking, and 3D similarity search.
• Quantum computational methods were employed to enhance nucleophilic activity. A total of 115 compounds were selected for experimental validation, all of which passed patentability assessment.
Results
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