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Biomolecules
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Advances in Protein-Ligand Interactions: From Structure, Function to Applications
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Advances in Protein-Ligand Interactions: From Structure, Function to Applications

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biophysics: Structure, Dynamics, and Function".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 18989

Special Issue Editor

Dr. Mateusz Banach

E-Mail Website1 Website2
Guest Editor
Department of Bioinformatics and Telemedicine, Faculty of Medicine, Jagiellonian University Medical College, Medyczna 7, 30-688 Kraków, Poland
Interests: bioinformatics; computational geometry; computer science; data analysis; data visualization; hydrophobic core; optimization algorithms; protein folding; protein-protein interaction; python programming; web services and databases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteins do not dwell in the void. Quite the opposite—their cellular environment is crowded with molecules. Likewise, many biological processes depend on the interaction between proteins and their neighborhood. They can form complexes with other proteins, small molecules, ions, nucleic acids and nearby fragments of the cell membrane. While we typically equate the word “ligand” with members of the small compound category, depending on the context, this nomenclature can be extended to the other types of complex partners as well.

The understanding and the prediction of the protein–ligand interactions (PLIs) lie at the foundation of the drug discovery process. To check whether the specific compound achieves the desired biological activity, one must perform an in vitro experiment. However, due to the large number of candidates (available from the various drug libraries), exhaustive screening in the lab is both time-consuming and prohibitively costly. Computational methods allow us to tackle this issue by narrowing the search space down to a manageable number of the most promising solutions. The ever-growing amount of chemical and biological data evokes new research opportunities, but also the need for the improvement of the PLI analysis and prediction approaches.

In this Special Issue, we collate reports on current advancements in the area of protein–ligand interaction. This includes, but is not limited to, protein surface exploration, binding site recognition, docking algorithms, molecular dynamics, de novo drug design, ADME studies, application of machine learning frameworks and the results of clinical trials.

Dr. Mateusz Banach
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 100 words) can be sent to the Editorial Office for announcement on this website.

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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • bioinformatics
  • compound libraries
  • computational biology
  • de novo drug design
  • drug discovery
  • ligand binding
  • machine learning
  • molecular docking
  • molecular dynamics
  • protein complexes

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Published Papers (7 papers)

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Research

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17 pages, 685 KiB  
Article
Advanced Quantification of Receptor–Ligand Interaction Lifetimes via Single-Molecule FRET Microscopy
by Lukas Schrangl, Vanessa Mühlgrabner, René Platzer, Florian Kellner, Josephine Wieland, Reinhard Obst, José L. Toca-Herrera, Johannes B. Huppa, Gerhard J. Schütz and Janett Göhring
Biomolecules 2024, 14(8), 1001; https://doi.org/10.3390/biom14081001 - 13 Aug 2024
Viewed by 1476
Abstract
Receptor–ligand interactions at cell interfaces initiate signaling cascades essential for cellular communication and effector functions. Specifically, T cell receptor (TCR) interactions with pathogen-derived peptides presented by the major histocompatibility complex (pMHC) molecules on antigen-presenting cells are crucial for T cell activation. The binding [...] Read more.
Receptor–ligand interactions at cell interfaces initiate signaling cascades essential for cellular communication and effector functions. Specifically, T cell receptor (TCR) interactions with pathogen-derived peptides presented by the major histocompatibility complex (pMHC) molecules on antigen-presenting cells are crucial for T cell activation. The binding duration, or dwell time, of TCR–pMHC interactions correlates with downstream signaling efficacy, with strong agonists exhibiting longer lifetimes compared to weak agonists. Traditional surface plasmon resonance (SPR) methods quantify 3D affinity but lack cellular context and fail to account for factors like membrane fluctuations. In the recent years, single-molecule Förster resonance energy transfer (smFRET) has been applied to measure 2D binding kinetics of TCR–pMHC interactions in a cellular context. Here, we introduce a rigorous mathematical model based on survival analysis to determine exponentially distributed receptor–ligand interaction lifetimes, verified through simulated data. Additionally, we developed a comprehensive analysis pipeline to extract interaction lifetimes from raw microscopy images, demonstrating the model’s accuracy and robustness across multiple TCR–pMHC pairs. Our new software suite automates data processing to enhance throughput and reduce bias. This methodology provides a refined tool for investigating T cell activation mechanisms, offering insights into immune response modulation. Full article
(This article belongs to the Special Issue Advances in Protein-Ligand Interactions: From Structure, Function to Applications)
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16 pages, 3173 KiB  
Article
Subtype-Specific Ligand Binding and Activation Gating in Homomeric and Heteromeric P2X Receptors
by Xenia Brünings, Ralf Schmauder, Ralf Mrowka, Klaus Benndorf and Christian Sattler
Biomolecules 2024, 14(8), 942; https://doi.org/10.3390/biom14080942 - 2 Aug 2024
Cited by 1 | Viewed by 1775
Abstract
P2X receptors are ATP-activated, non-specific cation channels involved in sensory signalling, inflammation, and certain forms of pain. Investigations of agonist binding and activation are essential for comprehending the fundamental mechanisms of receptor function. This encompasses the ligand recognition by the receptor, conformational changes [...] Read more.
P2X receptors are ATP-activated, non-specific cation channels involved in sensory signalling, inflammation, and certain forms of pain. Investigations of agonist binding and activation are essential for comprehending the fundamental mechanisms of receptor function. This encompasses the ligand recognition by the receptor, conformational changes following binding, and subsequent cellular signalling. The ATP-induced activation of P2X receptors is further influenced by the concentration of Mg2+ that forms a complex with ATP. To explore these intricate mechanisms, two new fluorescently labelled ATP derivatives have become commercially available: 2-[DY-547P1]-AHT-ATP (fATP) and 2-[DY-547P1]-AHT-α,βMe-ATP (α,βMe-fATP). We demonstrate a subtype-specific pattern of ligand potency and efficacy on human P2X2, P2X3, and P2X2/3 receptors with distinct relations between binding and gaiting. Given the high in vivo concentrations of Mg2+, the complex formed by Mg2+ and ATP emerges as an adequate ligand for P2X receptors. Utilising fluorescent ligands, we observed a Mg2+-dependent reduction in P2X2 receptor activation, while binding remained surprisingly robust. In contrast, P2X3 receptors initially exhibited decreased activation at high Mg2+ concentrations, concomitant with increased binding, while the P2X2/3 heteromer showed a hybrid effect. Hence, our new fluorescent ATP derivatives are powerful tools for further unravelling the mechanism underlying ligand binding and activation gating in P2X receptors. Full article
(This article belongs to the Special Issue Advances in Protein-Ligand Interactions: From Structure, Function to Applications)
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20 pages, 4609 KiB  
Article
In Silico Study of Camptothecin-Based Pro-Drugs Binding to Human Carboxylesterase 2
by Frank Beierlein, Anselm H. C. Horn, Heinrich Sticht, Andriy Mokhir and Petra Imhof
Biomolecules 2024, 14(2), 153; https://doi.org/10.3390/biom14020153 - 27 Jan 2024
Cited by 1 | Viewed by 2108
Abstract
Pro-drugs, which ideally release their active compound only at the site of action, i.e., in a cancer cell, are a promising approach towards an increased specificity and hence reduced side effects in chemotherapy. A popular form of pro-drugs is esters, which are activated [...] Read more.
Pro-drugs, which ideally release their active compound only at the site of action, i.e., in a cancer cell, are a promising approach towards an increased specificity and hence reduced side effects in chemotherapy. A popular form of pro-drugs is esters, which are activated upon their hydrolysis. Since carboxylesterases that catalyse such a hydrolysis reaction are also abundant in normal tissue, it is of great interest whether a putative pro-drug is a probable substrate of such an enzyme and hence bears the danger of being activated not just in the target environment, i.e., in cancer cells. In this work, we study the binding mode of carboxylesters of the drug molecule camptothecin, which is an inhibitor of topoisomerase I, of varying size to human carboxylesterase 2 (HCE2) by molecular docking and molecular dynamics simulations. A comparison to irinotecan, known to be a substrate of HCE2, shows that all three pro-drugs analysed in this work can bind to the HCE2 protein, but not in a pose that is well suited for subsequent hydrolysis. Our data suggest, moreover, that for the irinotecan substrate, a reactant-competent pose is stabilised once the initial proton transfer from the putative nucleophile Ser202 to the His431 of the catalytic triad has already occurred. Our simulation work also shows that it is important to go beyond the static models obtained from molecular docking and include the flexibility of enzyme–ligand complexes in solvents and at a finite temperature. Under such conditions, the pro-drugs studied in this work are unlikely to be hydrolysed by the HCE2 enzyme, indicating a low risk of undesired drug release in normal tissue. Full article
(This article belongs to the Special Issue Advances in Protein-Ligand Interactions: From Structure, Function to Applications)
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12 pages, 1436 KiB  
Article
Molecular Insight into Ligand Binding and Transport by the Lentil Lipid Transfer Protein Lc-LTP2: The Role of Basic Amino Acid Residues at Opposite Entrances to the Hydrophobic Cavity
by Daria N. Melnikova, Ivan V. Bogdanov, Andrey E. Potapov, Anna S. Alekseeva, Ekaterina I. Finkina and Tatiana V. Ovchinnikova
Biomolecules 2023, 13(12), 1699; https://doi.org/10.3390/biom13121699 - 24 Nov 2023
Cited by 1 | Viewed by 1611
Abstract
Lipid transfer proteins (LTPs) realize their functions in plants due to their ability to bind and transport various ligands. Structures of many LTPs have been studied; however, the mechanism of ligand binding and transport is still not fully understood. In this work, we [...] Read more.
Lipid transfer proteins (LTPs) realize their functions in plants due to their ability to bind and transport various ligands. Structures of many LTPs have been studied; however, the mechanism of ligand binding and transport is still not fully understood. In this work, we studied the role of Lys61 and Lys81 located near the “top” and “bottom” entrances to the hydrophobic cavity of the lentil lipid transfer protein Lc-LTP2, respectively, in these processes. Using site-directed mutagenesis, we showed that both amino acid residues played a key role in lipid binding to the protein. In experiments with calcein-loaded liposomes, we demonstrated that both the above-mentioned lysine residues participated in the protein interaction with model membranes. According to data obtained from fluorescent spectroscopy and TNS probe displacement, both amino acid residues are necessary for the ability of the protein to transfer lipids between membranes. Thus, we hypothesized that basic amino acid residues located at opposite entrances to the hydrophobic cavity of the lentil Lc-LTP2 played an important role in initial protein–ligand interaction in solution as well as in protein–membrane docking. Full article
(This article belongs to the Special Issue Advances in Protein-Ligand Interactions: From Structure, Function to Applications)
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21 pages, 3457 KiB  
Article
The Blocking of Drug Resistance Channels by Selected Hydrophobic Statins in Chemoresistance Human Melanoma
by Wojciech Placha, Piotr Suder, Agnieszka Panek, Patrycja Bronowicka-Adamska, Marta Zarzycka, Małgorzata Szczygieł, Jacek Zagajewski and Monika Weronika Piwowar
Biomolecules 2023, 13(12), 1682; https://doi.org/10.3390/biom13121682 - 21 Nov 2023
Viewed by 2069
Abstract
Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of hydrophobic statins to inhibit drug resistance (Pgp protein). In a chemoresistance melanoma cell model, viability, [...] Read more.
Despite the development of modern drugs, drug resistance in oncology remains the main factor limiting the curability of patients. This paper shows the use of a group of hydrophobic statins to inhibit drug resistance (Pgp protein). In a chemoresistance melanoma cell model, viability, necroptosis with DNA damage, the absorption of the applied pharmaceuticals, and the functional activity of the ABCB1 drug transporter after administration of docetaxel or docetaxel with a selected hydrophobic statin were studied. Taxol-resistant human melanoma cells from three stages of development were used as a model: both A375P and WM239A metastatic lines and radial growth phase WM35 cells. An animal model (Mus musculus SCID) was developed for the A375P cell line. The results show that hydrophobic statins administered with docetaxel increase the accumulation of the drug in the tumor cell a.o. by blocking the ABCB1 channel. They reduce taxol-induced drug resistance. The tumor size reduction was observed after the drug combination was administrated. It was shown that the structural similarity of statins is of secondary importance, e.g., pravastatin and simvastatin. Using cytostatics in the presence of hydrophobic statins increases their effectiveness while reducing their overall toxicity. Full article
(This article belongs to the Special Issue Advances in Protein-Ligand Interactions: From Structure, Function to Applications)
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26 pages, 12805 KiB  
Article
Pharmacophore-Based Screening, Molecular Docking, and Dynamic Simulation of Fungal Metabolites as Inhibitors of Multi-Targets in Neurodegenerative Disorders
by Danish Iqbal, Mohammed Alsaweed, Qazi Mohammad Sajid Jamal, Mohammad Rehan Asad, Syed Mohd Danish Rizvi, Moattar Raza Rizvi, Hind Muteb Albadrani, Munerah Hamed, Sadaf Jahan and Hadeel Alyenbaawi
Biomolecules 2023, 13(11), 1613; https://doi.org/10.3390/biom13111613 - 4 Nov 2023
Cited by 8 | Viewed by 2728
Abstract
Neurodegenerative disorders, such as Alzheimer’s disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal [...] Read more.
Neurodegenerative disorders, such as Alzheimer’s disease (AD), negatively affect the economic and psychological system. For AD, there is still a lack of disease-altering treatments and promising cures due to its complex pathophysiology. In this study, we computationally screened the natural database of fungal metabolites against three known therapeutic target proteins of AD. Initially, a pharmacophore-based, drug-likeness category was employed for screening, and it filtered the 14 (A–N) best hits out of 17,544 fungal metabolites. The 14 best hits were docked individually against GSK-3β, the NMDA receptor, and BACE-1 to investigate the potential of finding a multitarget inhibitor. We found that compounds B, F, and L were immuno-toxic, whereas E, H, I, and J had a higher LD50 dose (5000 mg/kg). Among the examined metabolites, the Bisacremine-C (compound I) was found to be the most active molecule against GSK-3β (ΔG: −8.7 ± 0.2 Kcal/mol, Ki: 2.4 × 106 M−1), NMDA (ΔG: −9.5 ± 0.1 Kcal/mol, Ki: 9.2 × 106 M−1), and BACE-1 (ΔG: −9.1 ± 0.2 Kcal/mol, Ki: 4.7 × 106 M−1). It showed a 25-fold higher affinity with GSK-3β, 6.3-fold higher affinity with NMDA, and 9.04-fold higher affinity with BACE-1 than their native ligands, respectively. Molecular dynamic simulation parameters, such as RMSD, RMSF, Rg, and SASA, all confirmed that the overall structures of the targeted enzymes did not change significantly after binding with Bisacremine-C, and the ligand remained inside the binding cavity in a stable conformation for most of the simulation time. The most significant hydrophobic contacts for the GSK-3β-Bisacremine-C complex are with ILE62, VAL70, ALA83, and LEU188, whereas GLN185 is significant for H-bonds. In terms of hydrophobic contacts, TYR184 and PHE246 are the most important, while SER180 is vital for H-bonds in NMDA-Bisacremine-C. THR232 is the most crucial for H-bonds in BACE-1-Bisacremine-C and ILE110-produced hydrophobic contacts. This study laid a foundation for further experimental validation and clinical trials regarding the biopotency of Bisacremine-C. Full article
(This article belongs to the Special Issue Advances in Protein-Ligand Interactions: From Structure, Function to Applications)
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Review

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30 pages, 11199 KiB  
Review
Inhibitors of SARS-CoV-2 Main Protease (Mpro) as Anti-Coronavirus Agents
by Agnieszka Zagórska, Anna Czopek, Monika Fryc and Jakub Jończyk
Biomolecules 2024, 14(7), 797; https://doi.org/10.3390/biom14070797 - 4 Jul 2024
Cited by 11 | Viewed by 4967
Abstract
The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it a significant target for developing antiviral drugs. The inhibition of SARS-CoV-2 Mpro has emerged as a promising approach for developing therapeutic [...] Read more.
The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it a significant target for developing antiviral drugs. The inhibition of SARS-CoV-2 Mpro has emerged as a promising approach for developing therapeutic agents to treat COVID-19. This review explores the structure of the Mpro protein and analyzes the progress made in understanding protein–ligand interactions of Mpro inhibitors. It focuses on binding kinetics, origin, and the chemical structure of these inhibitors. The review provides an in-depth analysis of recent clinical trials involving covalent and non-covalent inhibitors and emerging dual inhibitors targeting SARS-CoV-2 Mpro. By integrating findings from the literature and ongoing clinical trials, this review captures the current state of research into Mpro inhibitors, offering a comprehensive understanding of challenges and directions in their future development as anti-coronavirus agents. This information provides new insights and inspiration for medicinal chemists, paving the way for developing more effective Mpro inhibitors as novel COVID-19 therapies. Full article
(This article belongs to the Special Issue Advances in Protein-Ligand Interactions: From Structure, Function to Applications)
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