Abstract
Acute lymphoblastic leukemia (ALL) remains the most common pediatric malignancy worldwide. Standard protocols such as BFM and GBTLI rely on long-established cytotoxic agents, yet novel targeted compounds have recently entered phase I/II trials. Despite these advances, no prior study has systematically compared the pharmacokinetic, ADMET, and quantum descriptor profiles of protocol-based drugs versus emerging clinical-phase agents. This study addresses that gap by integrating pharmacoinformatic and quantum-chemical approaches to highlight differences with potential clinical implications. We retrieved all small-molecule drugs from the BFM/GBTLI 2009 protocols and a representative set of phase I/II investigational compounds for pediatric ALL. In silico tools were used to assess physicochemical properties, ADMET (absorption, distribution, metabolism, excretion, and toxicity) profiles, and quantum chemical descriptors. We evaluated physicochemical and pharmacokinetic properties, including solubility, permeability, metabolic liabilities, and toxicity risks. Quantum chemical descriptors were calculated with density functional theory (DFT) to assess molecular reactivity (HOMO, LUMO, gap, dipole moment, electrophilicity). Multivariate analyses were applied to compare and cluster drug profiles. The comparative analysis revealed significant variability between guideline and clinical-phase compounds. Clinical-phase compounds generally exhibited higher molecular weight and lipophilicity, together with greater variability in permeability and solubility-related descriptors, indicating potential formulation and bioavailability challenges. Several investigational agents were identified as P-gp substrates and hERG inhibitors, suggesting increased risk of efflux-mediated resistance and cardiotoxicity. Quantum chemical analysis revealed that phase I/II compounds (e.g., Pelabresib, Molibresib) displayed smaller HOMO–LUMO gaps and higher electrophilicity, consistent with higher theoretical reactivity, whereas guideline drugs (e.g., Vincristine, Methotrexate) showed more stable electronic profiles. Cluster analysis confirmed distinct grouping between guideline and clinical-phase compounds. This in silico comparison integrates pharmacoinformatic and quantum descriptor analyses of established and emerging ALL therapeutics. By revealing key differences in drug-likeness, ADMET, and electronic reactivity, the study provides a comparative framework that may support the prioritization, optimization, and clinical translation of next-generation therapies for pediatric ALL.
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Acknowledgements
The authors also would like to thank for the support of the High-Performance Processing Nucleus (NPAD) of the UFRN/Brazil, CAPES/Brazil and CNPQ/Brazil.
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The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through large group Research Project under grant number RGP2/413/46.
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Ian A. F. Bahia contributed to conceptualization, methodology, and original draft preparation. Maria K. da Silva contributed to data curation, investigation, and formal analysis. Emad Rashad Sindi contributed to methodology and validation. João F. Rodrigues-Neto contributed to software, data analysis, and visualization. Edilson D. da Silva Jr. contributed to investigation and resources. Taha Alqahtani contributed to validation and critical review of the manuscript. Yewulsew Kebede Tiruneh contributed to supervision, project administration, and critical revision of the manuscript. Magdi E. A. Zaki contributed to supervision, funding acquisition, and final approval of the manuscript. Umberto L. Fulco contributed to conceptualization, methodology, and manuscript review. Jonas I. N. Oliveira contributed to formal analysis, writing—review and editing. All authors read and approved the final manuscript.
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Bahia, I.A.F., da Silva, M.K., Sindi, E.R. et al. Comparative pharmacoinformatic and quantum descriptor insights from BFM/GBTLI guidelines to phase I/II compounds for acute lymphoblastic leukemia (ALL). Sci Rep (2026). https://doi.org/10.1038/s41598-026-36374-9
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DOI: https://doi.org/10.1038/s41598-026-36374-9
