{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:57:13Z","timestamp":1785427033152,"version":"3.56.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009392","name":"Prince Sattam Bin Abdulaziz University","doi-asserted-by":"publisher","award":["PSAU\/2025\/03\/37204"],"award-info":[{"award-number":["PSAU\/2025\/03\/37204"]}],"id":[{"id":"10.13039\/100009392","id-type":"DOI","asserted-by":"publisher"}]},{"award":["PSAU\/2025\/03\/37204"],"award-info":[{"award-number":["PSAU\/2025\/03\/37204"]}],"id":[{"id":"https:\/\/ror.org\/04jt46d36","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Poly(ADP-ribose) polymerase 1 (PARP1) is an important therapeutic target in DNA repair-deficient cancers, but discovery of new inhibitors remains constrained by scaffold convergence, tolerability limits, and acquired resistance. This study aimed to develop an interpretable, reliability-stratified cheminformatics workflow for PARP1 potency prioritization and structure-based follow-up. Methods: A curated ChEMBL dataset of 3339 PARP1 inhibitors was encoded using RDKit 2D descriptors and Avalon fingerprints (1143 initial features), then reduced to 132 informative variables by Random Forest-based feature selection. Five regression models were optimized, including a stacked ensemble. Model interpretation was performed using permutation feature importance and SHAP. External near-domain corroboration was assessed using a stringent PubChem similarity expansion (Tanimoto &gt; 0.90) around sub-10 nM seed compounds, followed by comparison with retrievable experimental PARP1 activity values. Top scaffold-diverse candidates were further evaluated by complementary docking against PARP1 (PDB: 4R6E) using AutoDock Vina and cavity-guided docking through the SwissDock platform. Results: The stacked ensemble achieved the best held-out performance (test R2 = 0.723; RMSE = 0.610 pIC50 units), with 83.7% of test predictions within \u22640.75 pIC50 units and only 2.7% exceeding 1.5 pIC50 units. PubChem similarity expansion retrieved approximately 32,450 analogs, of which 3349 were predicted to have IC50 \u2264 10 nM. Among 366 compounds with retrievable experimental PARP1 activity values, predicted versus experimental pIC50 showed a positive association (R2 = 0.124; Pearson r = 0.479), with RMSE = 0.491 and MAE = 0.330 pIC50 units. Three ligands\u2014CID 168873053, CID 175154210, and CID 172894737\u2014showed the strongest complementary docking support and pocket-consistent poses relative to niraparib. Conclusions: This workflow provides a transparent and practically useful framework for near-domain PARP1 inhibitor prioritization. The combined QSAR, explainability, external corroboration, and docking strategy supports shortlist generation for experimental follow-up.<\/jats:p>","DOI":"10.3390\/ph19040584","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T09:40:31Z","timestamp":1775554831000},"page":"584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interpretable QSAR and Complementary Docking for PARP1 Inhibitor Prioritization: Reliability Stratification and Near-Domain Screening"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8053-9759","authenticated-orcid":false,"given":"Alaa M.","family":"Elsayad","sequence":"first","affiliation":[{"name":"Biomedical Group, Department of Electrical Engineering, College of Engineering, Prince Sattam Bin Abdulaziz University, Wadi Alddawasir 11991, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled A.","family":"Elsayad","sequence":"additional","affiliation":[{"name":"Pharmacy Department, Cairo University Hospitals, Cairo University, Cairo 11662, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1146\/annurev-cancerbio-042324-103725","article-title":"Mechanism of action of PARP inhibitors","volume":"9","author":"Kim","year":"2025","journal-title":"Annu. 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