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| Format: | Preprint |
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2026
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| Online Access: | https://arxiv.org/abs/2605.03707 |
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| _version_ | 1866913090793111552 |
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| author | Khiari, Sofiene Mahmoud, Amr H. Lill, Markus A. |
| author_facet | Khiari, Sofiene Mahmoud, Amr H. Lill, Markus A. |
| contents | Scoring functions remain the principal bottleneck in molecular docking: they routinely fail to rank near-native poses above decoys, and their composite single-score design obscures the physicochemical basis of each ranking error. We present AgenticPosesRanker, an agentic AI framework that combines six deterministic, physically grounded analysis tools (interaction fingerprinting, solvent-accessible burial, conformational strain, steric-clash detection, unsatisfied-polar-atom penalty, and chemical-identity extraction) with large-language-model (GPT-5) chain-of-thought reasoning to evaluate and rank docking poses. On a curated benchmark of ten protein-ligand systems (162 poses) balanced by construction between Smina scoring-function successes and failures, the agent achieved 50.0% best-pose accuracy, matching the design-fixed Smina baseline of 50.0% and significantly exceeding a 7.7% uniformly random baseline (p < 0.001, one-sided exact binomial test). The balanced-benchmark accuracy decomposes symmetrically: the agent retained 80% (4/5) of the Smina-success systems and recovered 20% (1/5) of the Smina-failure systems, so the aggregate 50% reflects one regression offset by one recovery rather than any net improvement over the Smina reference. Decision-attribution analysis showed high alignment between the agent's self-reported tool weights and objective metric separations of the selected pose (median \r{ho} = +0.83), consistent across correct and incorrect outcomes, localising the performance ceiling to tool-suite coverage rather than reasoning inconsistency. These results establish a methodological template for evaluating agentic AI against objective ground truth in the natural sciences and position the framework as an interpretable curation layer for late-stage pose refinement in structure-based drug design. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2605_03707 |
| institution | arXiv |
| publishDate | 2026 |
| record_format | arxiv |
| spellingShingle | AgenticPosesRanker: An Agentic AI Framework for Physically Grounded Ranking of Protein-Ligand Docking Poses Khiari, Sofiene Mahmoud, Amr H. Lill, Markus A. Biomolecules I.2.1; I.2.8; J.3 Scoring functions remain the principal bottleneck in molecular docking: they routinely fail to rank near-native poses above decoys, and their composite single-score design obscures the physicochemical basis of each ranking error. We present AgenticPosesRanker, an agentic AI framework that combines six deterministic, physically grounded analysis tools (interaction fingerprinting, solvent-accessible burial, conformational strain, steric-clash detection, unsatisfied-polar-atom penalty, and chemical-identity extraction) with large-language-model (GPT-5) chain-of-thought reasoning to evaluate and rank docking poses. On a curated benchmark of ten protein-ligand systems (162 poses) balanced by construction between Smina scoring-function successes and failures, the agent achieved 50.0% best-pose accuracy, matching the design-fixed Smina baseline of 50.0% and significantly exceeding a 7.7% uniformly random baseline (p < 0.001, one-sided exact binomial test). The balanced-benchmark accuracy decomposes symmetrically: the agent retained 80% (4/5) of the Smina-success systems and recovered 20% (1/5) of the Smina-failure systems, so the aggregate 50% reflects one regression offset by one recovery rather than any net improvement over the Smina reference. Decision-attribution analysis showed high alignment between the agent's self-reported tool weights and objective metric separations of the selected pose (median \r{ho} = +0.83), consistent across correct and incorrect outcomes, localising the performance ceiling to tool-suite coverage rather than reasoning inconsistency. These results establish a methodological template for evaluating agentic AI against objective ground truth in the natural sciences and position the framework as an interpretable curation layer for late-stage pose refinement in structure-based drug design. |
| title | AgenticPosesRanker: An Agentic AI Framework for Physically Grounded Ranking of Protein-Ligand Docking Poses |
| topic | Biomolecules I.2.1; I.2.8; J.3 |
| url | https://arxiv.org/abs/2605.03707 |