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Advances in Protein Structure-Function and Drug Discovery
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Advances in Protein Structure-Function and Drug Discovery

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (20 March 2026) | Viewed by 6629

Special Issue Editors

Prof. Dr. Francesc Xavier Avilés

E-Mail Website
Guest Editor
Institute for Biotechnology and Biomedicine, Universitat Autònoma de Barcelona, Campus Universitari, Bellaterra, Cerdanyola del Vallès, 08193 Barcelona, Spain
Interests: proteolytic enzymes and inhibitors; natural/synthetic inhibitors and ligands; structure-function; proteomics; molecular imaging; drug-discovery and screening
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. F. Xavier Gomis-Rüth

E-Mail Website
Guest Editor
The Molecular Biology Institute of Barcelona (IBMB-CSIC), 08193 Barcelona, Spain
Interests: protein; proteolytic enzymes; peptidases and their zymogens

Special Issue Information

Dear Colleagues,

Proteins are among the most active, essential and sophisticated molecules in the biological world, and key players in the biotechnological and biomedical fields. The roles and functionality of a protein are generally strongly dependent of its defined amino acid sequence, modifications, tridimensional structure (tertiary, quaternary) and environment, that is from its precise structure. Because of this, the structure-function relationships of a protein are considered the core of its behavior and properties, both at the fundamental and biotech/biomed applicative levels. Such properties are also essential when the design and derivation of drugs (inhibitors, activators, regulators ...) is considered for a given protein, or a family of them, and have to be taken into account in the drug discovery procedures and approaches.

In the here launched Special Issue all these components will be considered to promote and select research works addressed to such issue, and particularly on the following items:

  • Novelties and refinements on protein structure, protein function and relationships, particularly when related with the discovery and characterization of protein drug-targets. Also, with the derivation or refinement of drugs or drug families from them.
  • Structure-based fundamentals of the functionality and specific role of proteins, and on the discovery of drugs that could act on its inhibition, activation or regulation.
  • Development and improvement of approaches to facilitate the discovery and derivation of protein-directed drugs or lead compounds, either from natural or synthetic resources.

Prof. Dr. Francesc Xavier Avilés
Prof. Dr. F. Xavier Gomis-Rüth
Guest Editors

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

  • protein structure
  • protein function
  • protein drug target
  • inhibition
  • protein structure-function
  • protein drug discovery
  • protein inhibition
  • protein activation
  • protein regulation
  • protein structure-function and evolution
  • protein structure-function engineering and design
  • protein structure-function and drug discovery

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (5 papers)

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Research

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37 pages, 5780 KB  
Article
Structural and Proteomic Analysis of the Mouse Cathepsin B-DARPin 4m3 Complex Reveals Species-Specific Binding Determinants
by Miki Zarić, Livija Tušar, Lovro Kramer, Olga Vasiljeva, Matej Novak, Francis Impens, Aleksandra Usenik, Kris Gevaert, Dušan Turk and Boris Turk
Int. J. Mol. Sci. 2025, 26(24), 11910; https://doi.org/10.3390/ijms262411910 - 10 Dec 2025
Viewed by 558
Abstract
Cathepsin B (CatB) is a lysosomal cysteine protease that plays a major role in various pathologies and is therefore considered a valuable therapeutic target. To address species-specific inhibitor challenges, we characterized the selective binding of designed ankyrin repeat protein (DARPin) 4m3 toward mouse [...] Read more.
Cathepsin B (CatB) is a lysosomal cysteine protease that plays a major role in various pathologies and is therefore considered a valuable therapeutic target. To address species-specific inhibitor challenges, we characterized the selective binding of designed ankyrin repeat protein (DARPin) 4m3 toward mouse cathepsin B (mCatB) over human CatB (hCatB). The mCatB–DARPin 4m3 complex was validated by size-exclusion chromatography (SEC), nano-differential scanning fluorimetry (nano-DSF), and surface plasmon resonance (SPR), revealing high affinity binding (KD = 65.7 nM) and potent inhibition (Ki = 26.7 nM; mixed competitive/noncompetitive). DARPin 4m3 showed no binding/inhibition toward hCatB. The 1.67 Å crystal structure of the complex—the first for mCatB—identified key interaction residues (e.g., I65/Q66 in mCatB vs. S65/M66 in hCatB) conferring selectivity. Proteomic analysis of endogenous substrates using a support vector machine (SVM) revealed greater similarity between mCatB and hCatB cleavages (Area Under the Curve (AUC) = 0.733) than between mCatB and other human cathepsins (AUC = 0.939–0.965). Clustering and SVM methods offer broadly applicable tools for protease specificity profiling in drug discovery. This study demonstrates the utility of DARPins for species-selective targeting and highlights the importance of integrated structural and proteomic approaches for dissecting protein–protein interactions. Full article
(This article belongs to the Special Issue Advances in Protein Structure-Function and Drug Discovery)
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17 pages, 4373 KB  
Article
Discovery and Characterization of Novel Non-Hydroxamate HDAC11 Inhibitors
by Aleksandra Kopranovic and Franz-Josef Meyer-Almes
Int. J. Mol. Sci. 2025, 26(13), 5950; https://doi.org/10.3390/ijms26135950 - 20 Jun 2025
Cited by 1 | Viewed by 1865
Abstract
Histone deacetylase 11 (HDAC11), the sole member of class IV HDACs, has gained prominence due to its unique enzymatic profile and pathological relevance in cancer, neurodegenerative, inflammatory diseases, and metabolic disorders. However, only a limited number of selective HDAC11 inhibitors have been identified, [...] Read more.
Histone deacetylase 11 (HDAC11), the sole member of class IV HDACs, has gained prominence due to its unique enzymatic profile and pathological relevance in cancer, neurodegenerative, inflammatory diseases, and metabolic disorders. However, only a limited number of selective HDAC11 inhibitors have been identified, and many of these contain a potentially mutagenic hydroxamic acid as a zinc-chelating motif. Consequently, there is an imperative to identify potent and selective non-hydroxamate HDAC11 inhibitors with improved physicochemical properties. In this study, we conducted an extensive experimental high-throughput screening of 10,281 structurally diverse compounds to identify novel HDAC11 inhibitors. Two promising candidates, caffeic acid phenethyl ester (CAPE) and compound 9SPC045H03, both lacking a hydroxamic acid warhead, were discovered, showing micromolar inhibitory potency (IC50 = 1.5 and 2.3 µM, respectively), fast and reversible binding, and remarkable isozyme selectivity. Molecular docking revealed distinct zinc-chelating mechanisms involving either carbonyl oxygen (CAPE) or pyridine nitrogen (9SPC045H03), in contrast to canonical hydroxamates. Both compounds are drug-like and exhibit favorable physicochemical and pharmacokinetic profiles, particularly beneficial water solubility and good adsorption, making them valuable starting points for further optimization. These findings open new avenues for the development of selective, non-hydroxamate HDAC11 inhibitors with potential therapeutic applications. Full article
(This article belongs to the Special Issue Advances in Protein Structure-Function and Drug Discovery)
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Review

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45 pages, 9433 KB  
Review
Drug Discovery Strategies for Kallikrein-Related Peptidases
by Tobias Dreyer, Daniela Schuster, Viktor Magdolen and Peter Goettig
Int. J. Mol. Sci. 2026, 27(1), 225; https://doi.org/10.3390/ijms27010225 - 25 Dec 2025
Viewed by 1569
Abstract
Kallikrein-related peptidases (KLKs) are hallmarks of higher vertebrates, in particular of mammals. While the 15 human KLKs occur in nearly all tissues and body fluids and participate in many physiological processes, they are also involved in severe diseases. Among them are prostate, ovarian [...] Read more.
Kallikrein-related peptidases (KLKs) are hallmarks of higher vertebrates, in particular of mammals. While the 15 human KLKs occur in nearly all tissues and body fluids and participate in many physiological processes, they are also involved in severe diseases. Among them are prostate, ovarian and breast cancer, as well as inherited skin and neurological disorders. Thus, KLKs have become targets for inhibitory compounds in academic and commercial research. The most prominent clinical biomarker and anti-cancer target for various approaches is PSA/KLK3. Already in the distant past, natural crude extracts were the source of medicine, while purified natural compounds and their derivatives are still the basis of about 50% of all pharmaceuticals. Nevertheless, structure-based rational design and high-throughput screening of natural and synthetic compound libraries are highly effective approaches for discovering lead compounds in the development of new drugs. Recently, computer-aided virtual or in silico screening has become a rapid method for such discoveries when combined with in vitro assays using protein targets or tests in cell cultures. To date, the successful implementation of artificial intelligence (AI) in the biosciences has significantly contributed to drug discovery. Our review focuses on state-of-the-art strategies and techniques in the context of KLK targets. Full article
(This article belongs to the Special Issue Advances in Protein Structure-Function and Drug Discovery)
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15 pages, 1208 KB  
Review
Is dUTPase Enzymatic Activity Truly Essential for Viability?
by Anatoly Glukhov, Ulyana Dzhus, Ilya Kolyadenko, Georgii Selikhanov and Azat Gabdulkhakov
Int. J. Mol. Sci. 2025, 26(19), 9260; https://doi.org/10.3390/ijms26199260 - 23 Sep 2025
Cited by 1 | Viewed by 927
Abstract
The study of protein enzymatic activities has always been a significant area of scientific and industrial research. The key steps typically undertaken in the characterization of a certain enzyme family include establishing the mechanism of catalysis, measuring kinetic parameters, determining structural organization and [...] Read more.
The study of protein enzymatic activities has always been a significant area of scientific and industrial research. The key steps typically undertaken in the characterization of a certain enzyme family include establishing the mechanism of catalysis, measuring kinetic parameters, determining structural organization and the architecture of the catalytic center, and subsequent classification. In this review, we tried to touch upon only a few points from the classical description of enzymes of the dUTPase family and added some additional functional properties of a number of representatives of this family. The existence of such extra functions raises questions about the reasons for this function duality. Based on the information known in the literature and our previous research, in this review, we conclude that the enzymatic activity of dUTPases supplements other functions independent of the hydrolysis reaction occurring in the catalytic center. In this context, it seems that dUTP acts not just as a substrate but as a signaling molecule, whose binding induces the realization of a special, non-enzymatic role of dUTPases. Full article
(This article belongs to the Special Issue Advances in Protein Structure-Function and Drug Discovery)
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Other

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11 pages, 741 KB  
Brief Report
Moonlighting Proteins: Some Hypotheses on the Structural Origin of Their Multifunctionality
by Juan Cedano, Mario Huerta, Angel Mozo-Villarias and Enrique Querol
Int. J. Mol. Sci. 2025, 26(21), 10375; https://doi.org/10.3390/ijms262110375 - 24 Oct 2025
Cited by 2 | Viewed by 1150
Abstract
Moonlighting proteins—single polypeptides performing multiple, often unrelated functions—are increasingly recognized as key players in human disease and microbial pathogenesis, making their identification crucial for understanding disease mechanisms and developing targeted therapies. This study addresses the unresolved question of how such multifunctionality evolves, focusing [...] Read more.
Moonlighting proteins—single polypeptides performing multiple, often unrelated functions—are increasingly recognized as key players in human disease and microbial pathogenesis, making their identification crucial for understanding disease mechanisms and developing targeted therapies. This study addresses the unresolved question of how such multifunctionality evolves, focusing on two potential structural mechanisms: Non-Orthologous Gene Displacement/Non-Homologous Isofunctional Enzymes (NOGD/NHIE), where evolutionarily unrelated proteins perform the same function, and Fold-Switching Proteins (FSP), which adopt alternative secondary structures to switch functions without sequence changes. We analyzed the overlap between known human moonlighting proteins (from MultitaskProtDB-II) and curated datasets of NOGD/NHIE (Non-Orthologous Gene Displacement/Non-Homologous Isofunctional Enzymes) and fold-switching proteins (FSPs), using Fisher’s exact test for statistical validation. Moonlighting proteins showed extraordinary enrichment for NOGD/NHIE (19.89% vs. 0.39% in non-moonlighting proteins; odds ratio = 63.1, p < 2.2 × 10−16) and strong enrichment for FSPs (6.99% vs. 0.26%; odds ratio = 28.7, p = 1.13 × 10−14), corresponding to ~51-fold and ~27-fold higher risks, respectively. These findings establish intrinsic structural plasticity—whether through evolutionary replacement (NOGD/NHIE) or conformational switching (FSP)—as a central mechanism enabling functional moonlighting in the human proteome. The results suggest that such plasticity facilitates functional innovation while preserving sequence integrity, and that both NOGD/NHIE and FSP features may serve as predictive signatures for identifying novel moonlighting proteins, particularly those with implications for disease mechanisms and therapeutic targeting. Full article
(This article belongs to the Special Issue Advances in Protein Structure-Function and Drug Discovery)
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