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For that purpose, our research group has recently developed a state-of-the-art framework  for molecular inference. This framework first constructs a prediction function for a fixed property using machine learning models, which is then simulated by mixed-integer linear programming to infer desired molecules. The accuracy of the framework heavily relies on the representation power of the descriptors. In this study, we highlight a typical class of non-isomorphic chemical graphs with reasonably different property values that cannot be distinguished by the standard \u201ctwo-layered (2L) model\" of . To address this distinguishability problem of the 2L model, we propose a novel family of descriptors, named <jats:italic>cycle-configuration (CC)<\/jats:italic>, which captures the notion of ortho\/meta\/para patterns that appear in aromatic rings, which was impossible in the framework so far. Extensive computational experiments show that with the new descriptors, we can construct prediction functions with similar or better performance for all 44 tested chemical properties, including 27 regression datasets and 17 classification datasets comparing with our previous studies, confirming the effectiveness of the CC descriptors. For inference, we also provide a system of linear constraints to formulate the CC descriptors as linear constraints. We demonstrate that a chemical graph with up to 50 non-hydrogen vertices can be inferred within a practical time frame.  <\/jats:p>","DOI":"10.1186\/s13321-025-01042-z","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T08:14:26Z","timestamp":1755504866000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cycle-configuration descriptors: a novel graph-theoretic approach to enhancing molecular inference"],"prefix":"10.1186","volume":"17","author":[{"given":"Bowen","family":"Song","sequence":"first","affiliation":[]},{"given":"Jianshen","family":"Zhu","sequence":"additional","affiliation":[]},{"given":"Naveed Ahmed","family":"Azam","sequence":"additional","affiliation":[]},{"given":"Kazuya","family":"Haraguchi","sequence":"additional","affiliation":[]},{"given":"Liang","family":"Zhao","sequence":"additional","affiliation":[]},{"given":"Tatsuya","family":"Akutsu","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,8,18]]},"reference":[{"issue":"12","key":"1042_CR1","doi-asserted-by":"publisher","first-page":"4977","DOI":"10.1021\/jm4004285","volume":"57","author":"A Cherkasov","year":"2014","unstructured":"Cherkasov A, Muratov EN, Fourches D, Varnek A, Baskin II, Cronin M, Dearden J, Gramatica P, Martin YC, Todeschini R, Consonni V, Kuz\u2019min VE, Cramer R, Benigni R, Yang C, Rathman J, Terfloth L, Gasteiger J, Richard A, Tropsha A (2014) Qsar modeling: Where have you been? where are you going to? 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