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Journal article
Nevermore: Target-Conditioned Protein–Ligand Representation Learning for Multi-Objective Lead Optimization with Database-Grounded Retrieval
Biology : open access journal, v 15(12), 971
21 Jun 2026
PMID: 42345827
Featured in Collection : Research Supported by Drexel Libraries' OA Programs
Abstract
Recently, there has been great interest in AI-based approaches for de novo design of novel drug candidates. However, the generation of useful lead drug candidate compounds requires more than predicting engagement with the desired protein target. Candidate molecules must also be anchored in the real world of medicinal chemistry for their synthesis and modification as well as satisfying multiple drug development-related criteria. Here, we present Nevermore, an AI target-conditioned, database-grounded workflow for prioritizing candidate ligands from large compound libraries. Nevermore uses a geometry-aware protein–ligand affinity oracle to score target-specific binding and perform sparse integer edits in count-based Morgan fingerprint space. Nevermore then retrieves the most structurally similar molecules from public chemical databases. This design enables multi-objective search over predicted affinity and absorption, distribution, metabolism, excretion, and toxicity (ADMET) proxies while keeping all candidates anchored to valid database compounds. We evaluated Nevermore’s performance across three biologically distinct targets: Menin, a protein-interaction target relevant to leukemia; SARS-CoV-2 Mpro, a viral cysteine protease relevant to antiviral discovery; and epidermal growth factor receptor (EGFR), a kinase-superfamily oncology target with extensive experimentally tested compounds. Nevermore retrieved candidate sets with favorable predicted affinity–property trade-offs. These results support database-grounded fingerprint steering as a practical computational strategy for lead prioritization and for generating testable molecular hypotheses, although the prioritized candidates remain predictions, requiring follow-up experimental validation.
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Details
- Title
- Nevermore: Target-Conditioned Protein–Ligand Representation Learning for Multi-Objective Lead Optimization with Database-Grounded Retrieval
- Creators
- Mohammad Saleh Refahi - Drexel University, Electrical and Computer EngineeringMilad Toutounchian - Drexel University, Information ScienceBahrad A Sokhansanj - Drexel University, Electrical and Computer EngineeringHyunwoo Ted Yoo - Drexel University, Electrical and Computer EngineeringJames R Brown - Drexel UniversityHai-Feng (Frank) Ji - Drexel University, ChemistryGail L Rosen (Corresponding Author) - Drexel University, Electrical and Computer Engineering
- Publication Details
- Biology : open access journal, v 15(12), 971
- Publisher
- MDPI
- Number of pages
- 33
- Grants
- Grant note
- University Research Computing Facility National Science Foundation: #1936791, #1919691, #2107108
This work was supported by the National Science Foundation under Grant Numbers #1936791, #1919691, and #2107108. We thank the University Research Computing Facility for their paid services.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Information Science; Electrical and Computer Engineering; Chemistry
- Web of Science ID
- WOS:001804125300001
- Other Identifier
- 991022193197304721
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