Molecular Handshakes: Engineering Protein–Ligand Interfaces for Precision Drug Design
A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".
Deadline for manuscript submissions: 28 February 2026 | Viewed by 8
Special Issue Editor
Special Issue Information
Dear Colleagues,
Protein–ligand interactions are central to modern drug discovery, shaping therapeutic efficacy, selectivity, and resistance. For decades, drug discovery has relied on simplified models of binding affinity and structure–activity relationships. However, proteins are not rigid scaffolds, and ligands are more than passive binders. Instead, these interactions are highly dynamic, context-dependent processes that dictate therapeutic efficacy, off-target effects, and resistance mechanisms. Recent technological breakthroughs have redefined how we study and engineer protein–ligand interfaces, shifting drug design from trial-and-error approaches to a precision-guided science.
Advances in computational chemistry, molecular dynamics (MD) simulations, cryo-electron microscopy, and high-resolution biophysical methods now allow us to probe interface flexibility and energetics in atomic detail. Parallel developments in machine learning and generative modeling expand the design space for novel ligands optimized not only for binding strength but also for selectivity, induced conformational changes, and downstream biological function. Together, these approaches are paving the way toward next-generation therapeutics capable of the fine-tuned modulation of protein targets in health and disease.
With this Special Issue, we aim to collate original research, methodological advances, reviews, and short communications that collectively expand our understanding of protein–ligand interface engineering in modern drug design. Contributions may include, but are not limited to, the following:
- Novel computational or experimental methods to characterize protein–ligand interfaces and their dynamics.
- Engineering strategies that optimize ligand specificity, affinity, and stability.
- Studies integrating molecular interactions with allosteric regulation, signaling pathways, and systems pharmacology.
- Applications of artificial intelligence, structural biology, or chemical biology to interface design.
- Translational insights into drug resistance, binding cooperativity, and modulation of previously "undruggable" targets.
By bringing together pioneering research across these themes, this Special Issue aims to showcase how reimagining protein–ligand interactions will redefine the future of precision therapeutics.
Dr. Tarun Jairaj Narwani
Guest Editor
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Keywords
- structure-based drug design (SBDD)
- AI-driven drug discovery
- protein–ligand dynamics
- molecular interface engineering
- structural biology
- chemical biology
- allosteric modulation
- undruggable targets and drug resistance
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