The transition from traditional two-dimensional (2D) cultures to three-dimensional (3D) systems represents one of the most transformative shifts in contemporary drug discovery. In recent years, 3D technologies have begun to close the long-standing gap between preclinical models and human biology—providing more physiologically relevant systems for compound evaluation, efficacy prediction, and the reduction of costly late-stage failures.

The Rise of 3D Cell Models

A recent review, “The Importance of 3D Cell Culture in Drug Discovery and Development” (Demirel & Koltuk, 2024), underscores the growing recognition that 3D cell models—such as multicellular spheroids and organoids—more accurately recapitulate cell–cell and cell–matrix interactions that 2D cultures lack. These complex microenvironments recreate in vivo–like gradients of oxygen, nutrients, and metabolites, yielding data that are far more predictive in drug screening and toxicity assessment.

Compared with monolayer cultures, spheroid models preserve the spatial organization and signaling pathways of living tissues. This is particularly critical in oncology, where 3D tumor spheroids mimic key features of real tumors, including hypoxic cores and proliferative outer layers. Such fidelity allows for a more realistic evaluation of therapeutic responses and, as the review highlights, could substantially improve the translation of preclinical findings to clinical outcomes.

To support this evolution, a growing number of research platforms now offer advanced 3D spheroid systems that integrate biomimetic scaffolds, microfluidic technology, and high-resolution imaging compatibility. These platforms are invaluable for high-content screening, compound profiling, and mechanistic analysis—providing a detailed view of how drugs behave in biologically relevant environments.

Expanding the Toolbox: Custom Cell Sources

A key enabler of 3D model development is access to robust and diverse cellular sources. Beyond conventional immortalized cell lines, researchers are increasingly employing primary and stem-cell-derived populations to create tissue-specific or disease-relevant systems. From liver and kidney to lung and immune microenvironments, these custom cell models expand the scope of 3D biology into fields such as regenerative medicine, immunotherapy, and toxicology. Comprehensive cell libraries now make it possible to tailor cellular composition, ensuring that 3D systems better reflect human physiology and disease complexity.

Data Meets Dimensionality: Machine Learning in 3D Drug Design

While 3D cell systems are transforming experimental biology, computational innovation is advancing in parallel. A 2024 doctoral dissertation, “Machine Learning for 3D Small-Molecule Drug Discovery” (Guan, University of Illinois), showcases how generative algorithms and geometric deep learning can now model and design drug candidates directly in 3D atomic space. By integrating protein pocket data with diffusion-based neural networks, tools such as TargetDiff and LinkerNet generate ligands that precisely match the three-dimensional features of target binding sites—ushering in a new era of AI-guided medicinal chemistry.

This computational revolution complements biological innovation. When combined, virtual 3D design and experimental 3D validation create a powerful discovery pipeline: algorithms propose optimized molecular structures, while spheroid and organoid systems provide the biologically relevant platforms to test them.

Toward Predictive, Integrated Discovery

Together, these advances point toward a unified vision of predictive and integrated drug discovery—one that merges computational precision with biological realism. Machine learning accelerates the journey from hypothesis to candidate, while 3D models refine the accuracy of early testing. Challenges remain, including scalability, protocol standardization, and reproducibility across laboratories.

Nonetheless, the momentum is unmistakable. The convergence of 3D cell culture and 3D computational design marks more than just incremental progress—it signifies a paradigm shift in how medicines are conceived, modeled, and validated. As both technologies continue to mature, their integration is poised to define the next decade of biomedical innovation, where molecules are designed in silico and validated in living, spatially accurate cellular systems.