Systematic Computational Optimization and Population Shift Analysis of 8-Substituted Adenosine Analogs: A Multi-Parameter Framework for Navigating the KRAS G12D Switch II Pocket

The therapeutic inhibition of the KRAS G12D mutation remains a paramount challenge in precision oncology, as the chemically inert and negatively charged aspartate residue at position 12 necessitates high-fidelity non-covalent intervention. In this study, we propose a rational design strategy based on an 8-aryl-adenosine scaffold, utilizing strategic C8-functionalization as a stereoelectronic “conformational lock.” By inducing a stable syn -conformation of the glycosidic bond, we effectively vectorize functional groups toward the Switch II cryptic pocket (SII-P), enabling critical molecular recognition patterns—specifically a bifurcated hydrogen-bonding network with the mutant Asp12—that are spatially inaccessible to natural adenosine. To navigate the chemical space of 100 rationally designed analogs, we implemented a multi-parameter computational framework integrating CNN-driven molecular docking via the GNINA engine with a novel Population Shift Analysis (PSA). Our results demonstrate a definitive library-wide thermodynamic migration toward superior binding affinities, with optimized candidates breaching the -5.0 kcal/mol threshold (reaching a minimum of -5.22 kcal/mol ). Statistical determinants reveal that this potency gain is orthogonal to molecular mass accumulation ( r = 0.24 ) and is instead driven by exceptional Lipophilic Ligand Efficiency ( LLE , r = -0.95 ), proving that binding efficacy is a direct consequence of precise structural vectorization. Among the evaluated ensemble, Acetamide and Mixed-Halogen derivatives are nominated as high-priority leads for experimental validation, exhibiting optimal electrostatic complementarity and sub-cavity occupancy. This study provides a robust, scalable blueprint for the transformation of simple nucleoside fragments into high-efficiency, site-directed leads targeting one of oncology’s most elusive and lethal targets.