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Molecular Handshakes: Engineering Protein–Ligand Interfaces for Precision Drug Design
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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: 20 September 2026 | Viewed by 500

Special Issue Editor

Dr. Tarun Jairaj Narwani

E-Mail Website
Guest Editor
Université Paris Cité and Université des Antilles and Université de la Réunion, BIGR, UMR_S1134, DSIMB Team, Inserm, F-75014 Paris, France
Interests: protein–ligand; protein structures; protein kinases

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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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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Published Papers (1 paper)

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Research

37 pages, 6519 KB  
Article
Decoupling Size from Shape: Cellular Sheaf Laplacians as Ligand Geometry Descriptors for Binding Affinity Prediction
by Ömer Akgüller, Mehmet Ali Balcı and Gabriela Cioca
Int. J. Mol. Sci. 2026, 27(9), 3786; https://doi.org/10.3390/ijms27093786 - 24 Apr 2026
Viewed by 271
Abstract
Binding affinity prediction in computational drug discovery is confounded by trivial correlations between molecular size and measured potency. We introduce cellular sheaf Laplacians as descriptors of ligand molecular geometry that quantify geometric frustration independent of system size. Sheaves are constructed over molecular graphs [...] Read more.
Binding affinity prediction in computational drug discovery is confounded by trivial correlations between molecular size and measured potency. We introduce cellular sheaf Laplacians as descriptors of ligand molecular geometry that quantify geometric frustration independent of system size. Sheaves are constructed over molecular graphs by assigning three-dimensional coordinate spaces to atoms and projection operators encoding ideal bonding geometry to edges; eigendecomposition of the resulting Laplacian yields spectral features measuring inconsistencies between local geometric constraints and global topology. Applied to 14,050 protein-ligand complexes from the PDBbind v2020 refined set, MW-residualized Sheaf features capture a statistically significant geometric signal (rpartial = 0.171, p<10−70) that is orthogonal to the Wiener index (r=0.013) and persists after controlling for both molecular weight and classical graph-theoretic descriptors (rpartial = 0.390, p<10−9). Sheaf spectral features alone achieve predictive performance (R2=0.403) approaching that of fourteen classical cheminformatics descriptors (R2=0.446), and their combination yields consistent improvements across the binding affinity spectrum (RMSE =1.43pKd). Permutation importance analysis confirms the Sheaf Frobenius norm as the second most influential descriptor after molecular weight. We introduce Topological Binding Efficiency as a size-normalized quality metric identifying ligands that achieve potent binding through geometric complementarity rather than molecular bulk. Gaussian mixture analysis of the maximum eigenvalue distribution among strong binders reveals two distinct spectral modes corresponding to planar aromatic and three-dimensional sp3-rich scaffolds, confirmed by significant differences in fraction of sp3 carbons and aromatic ring counts (p<10−8). As an intentionally ligand-centric framework, our approach complements rather than replaces protein-aware co-modelling architectures. This work establishes cellular sheaf theory as a principled framework for encoding molecular topology with statistically significant associations with binding affinity, providing interpretable geometric insights that are inaccessible to conventional molecular descriptors. Full article
(This article belongs to the Special Issue Molecular Handshakes: Engineering Protein–Ligand Interfaces for Precision Drug Design)
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