2026· The Innovation Drug Discovery· 0 citations· 124 references
TL;DR
By delineating how physics-based priors synergize with data-driven representation learning, this review provides a comprehensive roadmap for generating physically plausible and thermodynamically stable therapeutics, ultimately accelerating the transition of computationally designed molecules from in silico blueprints to viable clinical candidates.
Abstract
Targeted drug discovery is fundamentally bottlenecked by the challenge of accurately modeling complex biomolecular interactions, ranging from small-molecule ligand binding to high-order macromolecular assemblies. While traditional physics-based computational methods provide profound mechanistic insights, their clinical utility is frequently hampered by prohibitive computational costs and scalability limitations when addressing highly flexible, cross-scale systems. Conversely, the rapid emergence of pure deep learning offers unprecedented computational speed but suffers from a fundamental “black-box” nature, sometimes yielding physically improbable conformations—often referred to as “hallucinations”—that can pose challenges in real-world experimental validation. To bridge this critical translational gap, the integration of physical principles with artificial intelligence—Physics-Informed Deep Learning (PIDL)—is currently driving a fundamental transition from purely empirical approximations to rational, physically grounded design. This review constructs a strategic framework to critically evaluate these transformative advances, structured around three methodological pillars: (1) Physics-constrained optimization, which integrates thermodynamic principles and integrative experimental restraints at the output level to decode macromolecular dynamics; (2) Physics-encoded architectures, which embed appropriate SE(3) or E(3) geometric symmetries directly into neural network topologies for precise structural recognition; and (3) Physics-guided representations, which project discrete sequences into continuous physicochemical manifolds to enhance interaction prediction. By delineating how physics-based priors synergize with data-driven representation learning, this review not only synthesizes current algorithmic breakthroughs but also provides a comprehensive roadmap for generating physically plausible and thermodynamically stable therapeutics, ultimately accelerating the transition of computationally designed molecules from in silico blueprints to viable clinical candidates.
It is argued that, since physics-based simulations and machine learning provide complementary approximations to the underlying probability distribution associated with biomolecular recognition events, and they excel respectively in consistency with free-energy landscapes and state populations and in predictive accuracy, the central challenge for the coming decade will be integrating them into hybrid frameworks that are scalable and transferable.
R. Khalil, Elena Frasnetti, Han Kurt et al.· Journal of Physical Chemistr...· 0 citations
Modelling sequences both “dry” and in the presence of explicit potassium cations are suggested as a simple, practical way to sample alternative conformations and to expose disordered regions that current predictors tend to over-fold.
Deep neural network (DNN)‐based in silico models show great promise in predicting the properties and bioactivities of novel compounds, including small molecules. Among traditional approaches, structure‐based drug design (SBDD) remains a fundamental approach for drug discovery using molecular docking, scoring functions, and molecular dynamics simulations. However, these approaches are often constrained by limited flexibility, resolution, and generalizability. Geometric deep learning (GDL) offers a transformative alternative by enabling models to learn directly from non‐Euclidean molecular representations, such as graphs, point clouds, and meshes, capturing critical 3D spatial relationships inherent to protein–ligand interactions. This review highlights the theoretical underpinnings and practical applications of GDL in small‐molecule drug discovery, focusing on tasks including binding affinity prediction, virtual screening, de novo molecule generation, pose prediction, ADMET profiling, and protein flexibility modeling. We explore key GDL architectures, graph neural networks, SE(3)‐equivariant networks, 3D convolutional neural networks, point cloud models, and geometric transformers, and assess their performance across various drug discovery benchmarks. The integration of geometry‐aware AI models with experimental and computational workflows was also highlighted for its potential to streamline hit‐to‐lead optimization and advance rational drug design. Despite remarkable progress, the field faces challenges including limited high‐quality 3D structural datasets, protein flexibility representation, and the interpretability of deep models. Addressing these issues through hybrid modeling approaches, multi‐resolution learning, and self‐supervised training could further elevate GDL's impact. Ultimately, GDL stands at the frontier of AI‐enhanced pharmaceutical innovation, offering unprecedented precision, efficiency, and insight in the pursuit of next‐generation therapeutics.
A. Srivastav, Unnati Modi, Rahul Kumar et al.· Molecular Informatics· 1 citation
PML is introduced, a novel computational framework that describes a binding interface as a family of multiscale manifolds, and results indicate that much of what determines binding strength is encoded in the shape of the interface itself, and that a single geometric description serves both classes without hand-tailored features.
Xingjian Xu, Zhe Su, Guo-Wei Wei et al.· arXiv.org· 0 citations
Virtual screening (VS) on small molecules aims to identify promising drug candidates against protein targets from expansive chemical libraries by balancing the core requirements of accurate scoring and efficient search against the inherent trade‐off between accuracy and speed. This survey provides a comprehensive review of how Artificial Intelligence and Machine Learning (AI/ML) are redefining this landscape across three critical dimensions. First, we examine the evolution of AI‐driven scoring functions, which utilize AI/ML models to capture complex structure–activity relationships from massive biochemical datasets, significantly enhancing structure‐ and ligand‐based evaluations beyond traditional heuristics. Second, we summarize the emergence of efficient search algorithms that iteratively prioritize informative compounds to reduce search efforts by orders of magnitude. Third, we review the paradigm shift toward generative molecular design, making VS transition from screening fixed libraries to the
de novo
generation of molecules optimized for specific structural contexts and multi‐objective properties. This review outlines the transition toward end‐to‐end, adaptive discovery systems that ensure computational hits are biologically potent, structurally optimized, and synthetically accessible.
Yifei Wang, Nupur Bansal, Shiyun Wa et al.· WIREs Computational Molecula...· 0 citations
Current structure-based drug design generative models often struggle to faithfully recapitulate genuine ligand-protein binding interactions. Instead, under the coupling of implicit learning architectures and biased training data, they tend to learn spurious statistical correlations. To address this, we propose EIP-Diff (Explicit Interaction-Prompted Diffusion), an architecture featuring a novel explicit interaction-prompt embedding mechanism that is better suited for real-world target-specific drug design. This architecture replaces biased implicit learning with explicit, residue-level biological guidance, thereby promoting more fine-grained geometric fidelity and more precise interaction-aware conditioning. To fully realize the capabilities of EIP-Diff and provide a reliable basis for performance evaluation, we further constructed CrystalData set, which provides higher-fidelity and less-biased structural supervision than existing data sets. This explicit architecture markedly improves distribution consistency: even when trained on the crossdocked data set, EIP-Diff achieves the highest alignment with authentic pharmacological distributions among evaluated models. Training on CrystalData set further enhances this alignment and improves 3D geometric accuracy, while retaining strong controllability, high chemical space coverage, and near-perfect uniqueness. In addition, target-based validation on KAT6A and YTHDC1 confirmed that EIP-Diff accurately recapitulates native-like binding modes. Furthermore, in a real-world drug design task against IDO1, we successfully designed a novel lead compound with nanomolar potency (IC50 = 0.31 nM). These results demonstrate that the EIP-Diff architecture can explicitly leverage experimentally derived structural data and biologically meaningful interaction information for target-specific molecular generation, thereby enabling its effective application to real-world structure-based drug design.
Huabin Du, Mingyang Wang, M. Luo et al.· Journal of the American Chem...· 0 citations
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