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Nevermore: Target-Conditioned Protein–Ligand Representation Learning for Multi-Objective Lead Optimization with Database-Grounded Retrieval
Journal article   Open access   Peer reviewed

Nevermore: Target-Conditioned Protein–Ligand Representation Learning for Multi-Objective Lead Optimization with Database-Grounded Retrieval

Mohammad Saleh Refahi, Milad Toutounchian, Bahrad A Sokhansanj, Hyunwoo Ted Yoo, James R Brown, Hai-Feng (Frank) Ji and Gail L Rosen
Biology : open access journal, v 15(12), 971
21 Jun 2026
DOI: https://doi.org/10.3390/biology15120971
PMID: 42345827
Featured in Collection :   Research Supported by Drexel Libraries' OA Programs
url
https://doi.org/10.3390/biology15120971View
Published, Version of Record (VoR) Open Access Discount via Drexel Libraries Read and Publish Program 2026 Open CC BY V4.0

Abstract

target-conditioned molecular design protein-ligand affinity prediction contrastive representation learning multi-objective lead optimization database-grounded retrieval
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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