In silico Modeling of RNA-Based                             Spiegelmer Targeting Siglec-6 Receptors in Acute Myeloid Leukemia (AML)

Acute Myeloid Leukemia (AML) is a form of blood cancer in which myeloid progenitor cells mutate into abnormal myeloid blasts that multiply quickly, take up space within the bone marrow, and prevent the production of normal blood cells. Siglec-6 is a receptor strongly expressed on the surface of these cancer stem cells. Spiegelmers are synthetic mirror-image RNA aptamers of L-RNA that bind specifically to target molecules and exhibit high stability against nucleases. These spiegelmers could bind to the Siglec-6 receptor and, due to their L-form, may potentially evade nuclease degradation, thereby providing a foundation for novel targeted therapeutics. The 3D structure of Siglec-6 was modeled using AlphaFold 3 based on its amino acid sequence. The potential binding pockets on the surface of the protein were computed using P2Rank and ScanNet. Spiegelmers (S1=S5) were designed and structurally modeled using a multi-step process that included UNAfold for secondary structure prediction and ROSIE for tertiary structure modeling. Molecular docking simulations between Siglec-6 and spiegelmers were conducted to assess binding affinities and structural compatibility. Among the candidates, Spiegelmer S1 exhibited the most favorable interaction with Siglec-6, suggesting its potential as a lead molecule for targeted therapy. This computational pipeline provides a foundational framework for developing spiegelmer-guided CAR T-cell or aptamer-based therapies for AML, advancing precision medicine in hematologic oncology.