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Protein-Ligand Interactions
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Protein-Ligand Interactions

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 5134

Special Issue Editor

Dr. Małgorzata Maciążek-Jurczyk

E-Mail Website
Guest Editor
Department of Physical Pharmacy, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Sosnowiec, Poland
Interests: protein-ligand interactions; protein modification
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Interactions between proteins and ligands support the whole of biological science. The subject of protein–ligand interactions, especially serum protein, is one of the most exciting subjects in modern science. Due to the physicochemical properties of studied substances, there are numerous methods and techniques used in order to analyse their structure–function relationships. Understanding such interactions is crucial for gaining a fundamental knowledge base relating to cellular behaviour. The field of protein–ligand interaction studies is at an auspicious stage of development, as well as being in a very active growth phase. The main goal of this Special Issue is to provide a platform for publishing research on protein–ligand interactions, by using useful multi-disciplinary techniques applied in laboratories worldwide for investigating the basic principles and practical applications, especially in the pharmaceutical and biomedical fields.

Dr. Małgorzata Maciążek-Jurczyk
Guest Editor

Manuscript Submission Information

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Keywords

  • protein–ligand interactions
  • binding affinity
  • protein structure and function

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Published Papers (5 papers)

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Research

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13 pages, 5061 KiB  
Article
In Silico Investigation of Mineralocorticoid Receptor Antagonists: Insights into Binding Mechanisms and Structural Dynamics
by Julia J. Liang, Sara Cao, Andrew Hung, Assam El-Osta, Tom C. Karagiannis and Morag J. Young
Molecules 2025, 30(6), 1226; https://doi.org/10.3390/molecules30061226 - 9 Mar 2025
Viewed by 274
Abstract
The mineralocorticoid receptor (MR) is a steroid hormone receptor that plays a key role in regulating sodium and water homeostasis and blood pressure. MR antagonists are a guideline recommended for therapy for the treatment of hypertension and cardiovascular disease but can cause hyperkalaemia. [...] Read more.
The mineralocorticoid receptor (MR) is a steroid hormone receptor that plays a key role in regulating sodium and water homeostasis and blood pressure. MR antagonists are a guideline recommended for therapy for the treatment of hypertension and cardiovascular disease but can cause hyperkalaemia. Modelling was performed for binding of the endogenous ligands aldosterone and cortisol and MR antagonist spironolactone to the ligand binding domain (LBD) of the MR. A molecular docking screen of compounds that were structurally similar to known antagonists was performed, leading to the identification of two novel compounds, C79 and E67. Molecular dynamics (MD) assessed the dynamic interactions with C79, E76, endogenous ligands, and spironolactone with the MR ligand binding domain (LBD). Analysis of the protein backbone showed modest changes in the overall structure of the MR LBD in response to binding of antagonists, with movement in helix 12 consistent with previous observations. All ligands tested maintained stable binding within the MR LBD throughout the simulations. Hydrogen bond formation played a more prominent role in the binding of endogenous ligands compared to antagonists. MM-PBSA binding free energy calculations showed that all ligands had similar binding affinities, with binding facilitated by key residues within the binding site. The novel antagonists demonstrated similar binding properties to spironolactone, warranting further evaluation. This study provides insights into the molecular mechanisms of MR activation and inhibition, which can aid in the development of novel therapeutic strategies for cardiovascular diseases. Full article
(This article belongs to the Special Issue Protein-Ligand Interactions)
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15 pages, 2199 KiB  
Article
Human Serum Albumin and Human Serum Albumin Nanoparticles as Carriers of 10-(2′-Pyrimidyl)-3,6-diazaphenothiazine: In Vitro Spectroscopic Studies
by Aleksandra Owczarzy, Karolina Kulig, Beata Morak-Młodawska, Małgorzata Jeleń, Tammam Muhammetoglu, Wojciech Rogóż and Małgorzata Maciążek-Jurczyk
Molecules 2025, 30(2), 315; https://doi.org/10.3390/molecules30020315 - 15 Jan 2025
Viewed by 875
Abstract
Human serum albumin (HSA) plays a fundamental role in the human body, including the transport of exogenous and endogenous substances. HSA is also a biopolymer with a great medical and pharmaceutical potential. Due to nontoxicity and biocompatibility, this protein can be used as [...] Read more.
Human serum albumin (HSA) plays a fundamental role in the human body, including the transport of exogenous and endogenous substances. HSA is also a biopolymer with a great medical and pharmaceutical potential. Due to nontoxicity and biocompatibility, this protein can be used as a nanocarrier. 10-(2′-Pyrimidyl)-3,6-diazaphenothiazine (10-Pyr-3,6-DAPT) is a phenothiazine showing high anticancer potential in vitro against glioma, melanoma and breast cancer cells. Additionally, this compound is characterized by selectivity of action towards MCF-7 breast cancer and has low cytotoxicity towards normal cells. Considering the promising pharmacological potential of this compound and using spectroscopic techniques, HSA and human serum albumin nanoparticles (HSA-NP) were tested as carriers of this molecule. Based on the obtained data and the appropriate mathematical models (Stern-Volmer and Klotz models), it can be concluded that 10-Pyr-3,6-DAPT probably forms a weak (Ka = (5.24 ± 0.57) × 104 and Ka = (4.67 ± 0.59) × 104) for excitation wavelengths λex 275 nm and λex 295 nm, respectively) static complex (kq > 1010) with HSA (at Sudlow site II (subdomain IIIA), and the phenomenon of it having both strong therapeutic and toxic effects is possible. High encapsulation efficiency of 10-Pyr-3,6-DAPT into the HSA-NPs was obtained, and the changes in albumin secondary structure due to the presence of 10-Pyr-3,6-DAPT were registered. Based on the data presented, it can be concluded that due to the high toxic effects of 10-Pyr-3,6-DAPT, a better carrier may be HSA-NPs. Full article
(This article belongs to the Special Issue Protein-Ligand Interactions)
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22 pages, 7364 KiB  
Article
NMR Studies on the Structure of Yeast Sis1 and the Dynamics of Its Interaction with Ssa1-EEVD
by Carolina O. Matos, Glaucia M. S. Pinheiro, Icaro P. Caruso, Gisele C. Amorim, Fabio C. L. Almeida and Carlos H. I. Ramos
Molecules 2025, 30(1), 11; https://doi.org/10.3390/molecules30010011 - 24 Dec 2024
Viewed by 677
Abstract
HSP70 chaperones play pivotal roles in facilitating protein folding, refolding, and disaggregation through their binding and releasing activities. This intricate process is further supported by J-domain proteins (JDPs), also known as DNAJs or HSP40s, which can be categorized into classes A and B. [...] Read more.
HSP70 chaperones play pivotal roles in facilitating protein folding, refolding, and disaggregation through their binding and releasing activities. This intricate process is further supported by J-domain proteins (JDPs), also known as DNAJs or HSP40s, which can be categorized into classes A and B. In yeast, these classes are represented by Ydj1 and Sis1, respectively. While both classes stimulate the ATPase activity of Ssa1 (yeast HSP70) through the J-domain, only class B JDPs possess the unique ability to efficiently stimulate Ssa1 in disaggregation processes. The C-terminal EEVD motif of HSP70 plays a crucial role in mediating these interactions by connecting with both client proteins and JDPs. However, the removal of the EEVD motif disrupts the capacity of HSP70 to associate with class B JDPs, and the intricacies of the interaction between these two proteins remain incompletely understood. We employed NMR spectroscopy to investigate the structure and dynamics of the class B J domain protein (JDP) of S. cerevisiae (Sis1) complexed with an EEVD peptide of Ssa1. Our study is based on the extraordinary 70.5% residue assignment of the full-length (352 residues long) Sis1. Our findings revealed that EEVD binds to two distinct sites within the C-terminal domain I (CTDI) of Sis1, to the J domain and to the GF-rich loop located between the J domain and α-helix 6 (a structure identified by this work). We propose that the interaction between EEVD and Sis1 facilitates the dissociation of α-helix 6, promoting a conformational state that is more favorable for interaction with Ssa1. We also employed α-synuclein as a substrate to investigate the competitive nature between EEVD and the client protein. Our experimental findings provide evidence supporting the interaction of EEVD with the client protein at multiple sites and essential insights into the mechanistic cycle of class B JDPs. Full article
(This article belongs to the Special Issue Protein-Ligand Interactions)
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13 pages, 5173 KiB  
Article
Impact of Transglutaminase-Mediated Crosslinking on the Conformational Changes in a Dual-Protein System and IgE Reactivity of Soy Protein
by Guangliang Xing, Tianran Hui, Jia Liu and Siran Yang
Molecules 2024, 29(14), 3371; https://doi.org/10.3390/molecules29143371 - 18 Jul 2024
Cited by 1 | Viewed by 1425
Abstract
Transglutaminase (TGase)-catalyzed crosslinking has gained substantial traction as a novel strategy for reducing allergenic risk in food proteins, particularly within the realm of hypoallergenic food production. This study explored the impact of TGase crosslinking on conformational changes in a binary protein system composed [...] Read more.
Transglutaminase (TGase)-catalyzed crosslinking has gained substantial traction as a novel strategy for reducing allergenic risk in food proteins, particularly within the realm of hypoallergenic food production. This study explored the impact of TGase crosslinking on conformational changes in a binary protein system composed of soy protein isolate (SPI) and sodium caseinate (SC) at varying mass ratios (10:0, 7:3, 5:5, 3:7 (w/w)). Specifically, the immunoglobulin E (IgE) binding capacity of soy proteins within this system was examined. Prolonged TGase crosslinking (ranging from 0 h to 15 h) resulted in a gradual reduction in IgE reactivity across all SPI-SC ratios, with the order of IgE-binding capability as follows: SPI > SPI5-SC5 > SPI7-SC3 > SPI3-SC7. These alterations in protein conformation following TGase crosslinking, as demonstrated by variable intrinsic fluorescence, altered surface hydrophobicity, increased ultraviolet absorption and reduced free sulfhydryl content, were identified as the underlying causes. Additionally, ionic bonds were found to play a significant role in maintaining the structure of the dual-protein system after crosslinking, with hydrophobic forces and hydrogen bonds serving as supplementary forces. Generally, the dual-protein system may exhibit enhanced efficacy in reducing the allergenicity of soy protein. Full article
(This article belongs to the Special Issue Protein-Ligand Interactions)
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Review

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29 pages, 3039 KiB  
Review
Ligand-Induced Biased Activation of GPCRs: Recent Advances and New Directions from In Silico Approaches
by Shaima Hashem, Alexis Dougha and Pierre Tufféry
Molecules 2025, 30(5), 1047; https://doi.org/10.3390/molecules30051047 - 25 Feb 2025
Viewed by 988
Abstract
G-protein coupled receptors (GPCRs) are the largest family of membrane proteins engaged in transducing signals from the extracellular environment into the cell. GPCR-biased signaling occurs when two different ligands, sharing the same binding site, induce distinct signaling pathways. This selective signaling offers significant [...] Read more.
G-protein coupled receptors (GPCRs) are the largest family of membrane proteins engaged in transducing signals from the extracellular environment into the cell. GPCR-biased signaling occurs when two different ligands, sharing the same binding site, induce distinct signaling pathways. This selective signaling offers significant potential for the design of safer and more effective drugs. Although its molecular mechanism remains elusive, big efforts are made to try to explain this mechanism using a wide range of methods. Recent advances in computational techniques and AI technology have introduced a variety of simulations and machine learning tools that facilitate the modeling of GPCR signal transmission and the analysis of ligand-induced biased signaling. In this review, we present the current state of in silico approaches to elucidate the structural mechanism of GPCR-biased signaling. This includes molecular dynamics simulations that capture the main interactions causing the bias. We also highlight the major contributions and impacts of transmembrane domains, loops, and mutations in mediating biased signaling. Moreover, we discuss the impact of machine learning models on bias prediction and diffusion-based generative AI to design biased ligands. Ultimately, this review addresses the future directions for studying the biased signaling problem through AI approaches. Full article
(This article belongs to the Special Issue Protein-Ligand Interactions)
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