Transcriptome-Conditioned Personalized De Novo Drug Generation for AML Using Metaheuristic Assembly and Target-Driven Filtering

Abstract

Acute Myeloid Leukemia (AML) remains a clinical challenge due to its extreme molecular heterogeneity and high relapse rates. While precision medicine has introduced mutation-specific therapies, many patients still lack effective, personalized options. This paper presents a novel, end-to-end computational framework that bridges the gap between patient-specific transcriptomics and de novo drug discovery. By analyzing bulk RNA sequencing data from the TCGA-LAML cohort, the study utilized Weighted Gene Co-expression Network Analysis (WGCNA) to prioritize 20 high-value biomarkers, including metabolic transporters like HK3 and immune-modulatory receptors such as SIGLEC9. The physical structures of these targets were modeled using AlphaFold3, and druggable hotspots were quantitatively mapped via the DOGSiteScorer engine. Then developed a novel, reaction-first evolutionary metaheuristic algorithm as well as multi-objective optimization programming that assembles novel ligands from fragment libraries, guided by spatial alignment to these identified hotspots. The generative model produced structurally unique chemical entities with a strong bias toward drug-like space, as evidenced by QED scores peaking between 0.5 and 0.7. Validation through ADMET profiling and SwissDock molecular docking identified high-confidence candidates, such as Ligand L1, which achieved a binding free energy of -6.571 kcal/mol against the A08A96 biomarker. These results demonstrate that integrating systems biology with metaheuristic molecular assembly can produce pharmacologically viable, patient tailored leads, offering a scalable blueprint for precision oncology in AML and beyond