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Proteins in Drug Research
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Proteins in Drug Research

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

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 9823

Special Issue Editors

Dr. Csaba Hetényi

E-Mail Website1 Website2
Guest Editor
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Szigeti út 12, 7624 Pécs, Hungary
Interests: proteins; molecular structure; thermodynamics; drug design; chemoinformatics
Special Issues, Collections and Topics in MDPI journals
Dr. Uko Maran

E-Mail Website
Guest Editor
Institute of Chemistry, University of Tartu, Ravila 14A, 50411 Tartu, Estonia
Interests: theoretical and computer chemistry; malaria drug development
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteins play a central role in the pathomechanisms of diseases. In drug research, proteins are often targeted by small molecular drug candidates, and the application of protein drugs is emerging as well. The current Special Issue covers all aspects of drug research related to proteins. For example, molecular aspects of the role of proteins in the pathomechanism of diseases, the selection and validation of protein targets, the determination and calculation of protein structure, the development of assays, the selection of hits, and the design of small molecular lead compounds or the development of protein drugs will also be considered. Methods and applications that focus on the role of proteins in drug research are also of interest. Submission of both experimental and theoretical original research and reviews are welcome for the Special Issue.

Dr. Csaba Hetényi
Dr. Uko Maran
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 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. 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

  • proteomics
  • protein–protein interaction
  • protein–ligand interaction
  • crystallography
  • electron microscopy
  • NMR
  • molecular dynamics
  • docking
  • binding affinity
  • stability

Published Papers (5 papers)

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Research

18 pages, 3191 KiB  
Article
Cross-Linked α-Synuclein as Inhibitor of Amyloid Formation
by Nikoletta Murvai, Gabriella Gellen, András Micsonai, Gitta Schlosser and József Kardos
Int. J. Mol. Sci. 2023, 24(17), 13403; https://doi.org/10.3390/ijms241713403 - 29 Aug 2023
Viewed by 1091
Abstract
The aggregation and amyloid formation of α-synuclein is associated with Parkinson’s disease and other synucleinopathies. In its native, monomeric form α-synuclein is an intrinsically disordered protein represented by highly dynamic conformational ensembles. Inhibition of α-synuclein aggregation using small molecules, peptides, or proteins has [...] Read more.
The aggregation and amyloid formation of α-synuclein is associated with Parkinson’s disease and other synucleinopathies. In its native, monomeric form α-synuclein is an intrinsically disordered protein represented by highly dynamic conformational ensembles. Inhibition of α-synuclein aggregation using small molecules, peptides, or proteins has been at the center of interest in recent years. Our aim was to explore the effects of cross-linking on the structure and aggregation/amyloid formation properties of α-synuclein. Comparative analysis of available high-resolution amyloid structures and representative structural models and MD trajectory of monomeric α-synuclein revealed that potential cross-links in the monomeric protein are mostly incompatible with the amyloid forms and thus might inhibit fibrillation. Monomeric α-synuclein has been intramolecularly chemically cross-linked under various conditions using different cross-linkers. We determined the location of cross-links and their frequency using mass spectrometry and found that most of them cannot be realized in the amyloid structures. The inhibitory potential of cross-linked proteins has been experimentally investigated using various methods, including thioflavin-T fluorescence and transmission electron microscopy. We found that conformational constraints applied by cross-linking fully blocked α-synuclein amyloid formation. Moreover, DTSSP-cross-linked molecules exhibited an inhibitory effect on the aggregation of unmodified α-synuclein as well. Full article
(This article belongs to the Special Issue Proteins in Drug Research)
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16 pages, 5662 KiB  
Article
Direct Oral FXa Inhibitors Binding to Human Serum Albumin: Spectroscopic, Calorimetric, and Computational Studies
by Nory Mariño-Ocampo, Diego F. Rodríguez, Daniel Guerra Díaz, Daniel Zúñiga-Núñez, Yorley Duarte, Denis Fuentealba and Flavia C. Zacconi
Int. J. Mol. Sci. 2023, 24(5), 4900; https://doi.org/10.3390/ijms24054900 - 03 Mar 2023
Cited by 4 | Viewed by 1878
Abstract
Direct FXa inhibitors are an important class of bioactive molecules (rivaroxaban, apixaban, edoxaban, and betrixaban) applied for thromboprophylaxis in diverse cardiovascular pathologies. The interaction of active compounds with human serum albumin (HSA), the most abundant protein in blood plasma, is a key research [...] Read more.
Direct FXa inhibitors are an important class of bioactive molecules (rivaroxaban, apixaban, edoxaban, and betrixaban) applied for thromboprophylaxis in diverse cardiovascular pathologies. The interaction of active compounds with human serum albumin (HSA), the most abundant protein in blood plasma, is a key research area and provides crucial information about drugs’ pharmacokinetics and pharmacodynamic properties. This research focuses on the study of the interactions between HSA and four commercially available direct oral FXa inhibitors, applying methodologies including steady-state and time-resolved fluorescence, isothermal titration calorimetry (ITC), and molecular dynamics. The HSA complexation of FXa inhibitors was found to occur via static quenching, and the complex formation in the ground states affects the fluorescence of HSA, with a moderate binding constant of 104 M−1. However, the ITC studies reported significantly different binding constants (103 M−1) compared with the results obtained through spectrophotometric methods. The suspected binding mode is supported by molecular dynamics simulations, where the predominant interactions were hydrogen bonds and hydrophobic interactions (mainly π–π stacking interactions between the phenyl ring of FXa inhibitors and the indole moiety of Trp214). Finally, the possible implications of the obtained results regarding pathologies such as hypoalbuminemia are briefly discussed. Full article
(This article belongs to the Special Issue Proteins in Drug Research)
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18 pages, 2098 KiB  
Article
All-Atom Molecular Dynamics Simulations Indicated the Involvement of a Conserved Polar Signaling Channel in the Activation Mechanism of the Type I Cannabinoid Receptor
by Arijit Sarkar, Argha Mitra and Attila Borics
Int. J. Mol. Sci. 2023, 24(4), 4232; https://doi.org/10.3390/ijms24044232 - 20 Feb 2023
Viewed by 2126
Abstract
The type I cannabinoid G protein-coupled receptor (CB1, GPCR) is an intensely investigated pharmacological target, owing to its involvement in numerous physiological functions as well as pathological processes such as cancers, neurodegenerative diseases, metabolic disorders and neuropathic pain. In order to develop modern [...] Read more.
The type I cannabinoid G protein-coupled receptor (CB1, GPCR) is an intensely investigated pharmacological target, owing to its involvement in numerous physiological functions as well as pathological processes such as cancers, neurodegenerative diseases, metabolic disorders and neuropathic pain. In order to develop modern medications that exert their effects through binding to the CB1 receptor, it is essential to understand the structural mechanism of activation of this protein. The pool of atomic resolution experimental structures of GPCRs has been expanding rapidly in the past decade, providing invaluable information about the function of these receptors. According to the current state of the art, the activity of GPCRs involves structurally distinct, dynamically interconverting functional states and the activation is controlled by a cascade of interconnecting conformational switches in the transmembrane domain. A current challenge is to uncover how different functional states are activated and what specific ligand properties are responsible for the selectivity towards those different functional states. Our recent studies of the μ-opioid and β2-adrenergic receptors (MOP and β2AR, respectively) revealed that the orthosteric binding pockets and the intracellular surfaces of these receptors are connected through a channel of highly conserved polar amino acids whose dynamic motions are in high correlation in the agonist- and G protein-bound active states. This and independent literature data led us to hypothesize that, in addition to consecutive conformational transitions, a shift of macroscopic polarization takes place in the transmembrane domain, which is furnished by the rearrangement of polar species through their concerted movements. Here, we examined the CB1 receptor signaling complexes utilizing microsecond scale, all-atom molecular dynamics (MD) simulations in order to see if our previous assumptions could be applied to the CB1 receptor too. Apart from the identification of the previously proposed general features of the activation mechanism, several specific properties of the CB1 have been indicated that could possibly be associated with the signaling profile of this receptor. Full article
(This article belongs to the Special Issue Proteins in Drug Research)
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22 pages, 1997 KiB  
Article
Plk4 Is a Novel Substrate of Protein Phosphatase 5
by Edit Ábrahám, Zsuzsánna Réthi-Nagy, Péter Vilmos, Rita Sinka and Zoltán Lipinszki
Int. J. Mol. Sci. 2023, 24(3), 2033; https://doi.org/10.3390/ijms24032033 - 19 Jan 2023
Cited by 2 | Viewed by 2219
Abstract
The conserved Ser/Thr protein phosphatase 5 (PP5) is involved in the regulation of key cellular processes, including DNA damage repair and cell division in eukaryotes. As a co-chaperone of Hsp90, PP5 has been shown to modulate the maturation and activity of numerous oncogenic [...] Read more.
The conserved Ser/Thr protein phosphatase 5 (PP5) is involved in the regulation of key cellular processes, including DNA damage repair and cell division in eukaryotes. As a co-chaperone of Hsp90, PP5 has been shown to modulate the maturation and activity of numerous oncogenic kinases. Here, we identify a novel substrate of PP5, the Polo-like kinase 4 (Plk4), which is the master regulator of centriole duplication in animal cells. We show that PP5 specifically interacts with Plk4, and is able to dephosphorylate the kinase in vitro and in vivo, which affects the interaction of Plk4 with its partner proteins. In addition, we provide evidence that PP5 and Plk4 co-localize to the centrosomes in Drosophila embryos and cultured cells. We demonstrate that PP5 is not essential; the null mutant flies are viable without a severe mitotic phenotype; however, its loss significantly reduces the fertility of the animals. Our results suggest that PP5 is a novel regulator of the Plk4 kinase in Drosophila. Full article
(This article belongs to the Special Issue Proteins in Drug Research)
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15 pages, 2850 KiB  
Article
Association Mechanism and Conformational Changes in Trypsin on Its Interaction with Atrazine: A Multi- Spectroscopic and Biochemical Study with Computational Approach
by Arwa Ishaq A. Khayyat, Seema Zargar, Tanveer A. Wani, Muneeb U. Rehman and Azmat Ali Khan
Int. J. Mol. Sci. 2022, 23(10), 5636; https://doi.org/10.3390/ijms23105636 - 18 May 2022
Cited by 22 | Viewed by 1800
Abstract
Atrazine (ATR) is a herbicide globally used to eliminate undesired weeds. Herbicide usage leads to various adverse effects on human health and the environment. The primary source of herbicides in humans is the food laced with the herbicides. The ATR binding to trypsin [...] Read more.
Atrazine (ATR) is a herbicide globally used to eliminate undesired weeds. Herbicide usage leads to various adverse effects on human health and the environment. The primary source of herbicides in humans is the food laced with the herbicides. The ATR binding to trypsin (TYP) was investigated in this study to explore its binding potential and toxicity. In vitro interaction of ATR with TYP was studied using multi-spectroscopic methods, molecular docking, and enzyme kinetics to explore the mechanism of binding for the TYP-ATR system. The TYP-ATR complex revealed binding constants (103 M−1), suggesting a moderate binding. The free energy for the TYP-ATR complexes was negative, suggesting a spontaneous interaction. Thermodynamic parameters enthalpy (ΔH) and entropy (ΔS) obtained positive values for the TYP-ATR system suggesting hydrophobic interactions in the binding process. Micro-environmental and conformational changes in TYP molecules were induced on interaction with ATR. Reduced catalytic activity of TYP was observed after interaction with ATR owing to the changes in the secondary structure of the TYP. Full article
(This article belongs to the Special Issue Proteins in Drug Research)
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