Fragment-Based and Structure-Guided Discovery of Small-Molecule Anticancer Agents: From In Silico Design to Biological Validation

Fragment-based drug discovery (FBDD) has emerged as a rigorous and efficient strategy for identifying lead compounds against structurally defined biological targets. By starting from low-molecular-weight fragments with measurable binding affinity, FBDD enables broader exploration of chemical space relative to compound size and facilitates the design of highly selective inhibitors through fragment growing, merging, or linking. In oncology, structure-based virtual screening and fragment-based approaches have yielded inhibitors targeting kinases, epigenetic regulators, proteases, and protein–protein interaction interfaces, among others. The integration of computational tools with synthetic medicinal chemistry and cancer-relevant biological assays has accelerated the translation of fragment hits into pharmacologically active anticancer leads.

Despite the growing toolbox of in silico methods and the expanding repertoire of validated oncology targets, the transition from fragment hit to biologically validated anticancer lead remains methodologically heterogeneous and underreported in a structured, cross-target format. Many studies report computational workflows or biological outcomes in isolation, limiting the field’s capacity to benchmark approaches and identify best practices across target classes. This Research Topic aims to provide a dedicated forum for original research and critical reviews spanning the full discovery pipeline: from target selection and fragment screening to hit-to-lead optimization and validation in cancer-relevant biological models. By consolidating studies that bridge computational design with experimental pharmacology, this collection will serve as a resource for the anticancer drug discovery community and highlight emerging strategies that are reshaping precision oncology drug development.

This Research Topic welcomes original research articles, reviews, and systematic reviews addressing, but not limited to, the following themes:

• Fragment-based or structure-based virtual screening campaigns against oncologically relevant targets

• Computational workflows for fragment hit identification, growing, linking, or merging

• Synthesis and structure-activity relationship (SAR) studies of small-molecule anticancer leads

• Molecular docking, molecular dynamics simulation, and pharmacophore-based approaches for cancer target engagement

• Design of multitarget anticancer scaffolds and heterocyclic hybrids

• Structure-guided design of targeted protein degraders (PROTACs and molecular glues)

• Biological validation of small-molecule candidates in cancer cell lines or in vivo models.

Studies integrating computational and experimental approaches are especially encouraged. Contributions targeting understudied or emerging oncology targets are particularly welcome.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Data Report
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Fragment-based drug discovery (FBDD), Structure-guided drug design, Anticancer small molecules, Structure-activity relationship (SAR), Virtual screening, Targeted protein degraders (PROTACs), In silico lead optimization

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.