Benign by Design Chemistry: Re-inventing Ligand-Based Drug Design at the Edge of AI

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Published: 2026-02-20

Formatted citation

López-López E, Hernández-Estrada PI, Toto-Vazquez AN, Ávila-Martínez DV, Spjuth O, and Medina-Franco JL.. Benign by Design Chemistry: Re-inventing Ligand-Based Drug Design at the Edge of AI.
Drug Discovery Today. Accepted (2026).

Abstract

Ligand-based drug design (LBDD) has long driven therapeutic innovation; however, its traditional potency-centered paradigm often oversimplifies biological complexity. Advances in artificial now enable multi-objective strategies that integrate polypharmacology, safety, and environmental sustainability. Despite this progress a unified framework, systematically incorporating these dimensions within AI-augmented LBDD, is missing. Here, we propose that embedding benign-by-design principles into multi-objective optimization can enable the proactive mitigation of toxicity, off-target effects, and ecological impact from early design and discovery stages. This shift redefines LBDD as a complexity-aware and ethically grounded discipline capable of delivering safer and more sustainable therapeutics. Accordingly, the primary objective of this manuscript is to outline a unifying framework for AI-enabled LBDD that moves beyond potency-centered optimization by integrating efficacy, safety, sustainability, and societal impact.