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Pharmaceutics
Special Issues
Protein–Drug Interaction
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Protein–Drug Interaction

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 24816

Special Issue Editors

Dr. Fabrizio Dal Piaz

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Salerno, Salerno, Italy
Interests: drug target identification; protein–drug interaction; bioanalytical mass spectrometry; pharmacokinetics; proteomics; bioactive natural compounds
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Viviana Izzo

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Salerno, Salerno, Italy
Interests: biochemistry; protein structure and function; multi-enzymatic complexes; pharmacokinetics

Special Issue Information

Dear Colleagues,

Binding between bioactive compounds and proteins plays a pivotal role in many therapeutic or preventive approaches. In the first place, in fact, most drugs carry out their action through the direct modulation of the activity of proteins and protein complexes. Moreover, several proteins regulate the transport and distribution of drugs within organisms, tissues, and cells. Finally, the action of different enzymes determines the metabolism, the elimination and, in some cases, the activation of most exogenous bioactive substances. At the same time, several undesired effects of therapeutic treatments depend on off-target interactions. Therefore, a detailed understanding of the molecular mechanisms underlying the formation of drug/protein complexes and of the variations induced by this interaction on proteins’ activity and interactome is of utmost importance for drug discovery, pharmacology, pharmacotoxicology, and medicinal chemistry studies.

This Special Issue will include original papers and reviews that deal with the topic of drug/protein interaction under different points of view. The issue is open to contributions that discuss results obtained using experimental approaches such as crystallography, NMR, surface plasmon resonance, proteomics, bioinformatics, cell biology, clinical pharmacology, and many others. The aim is to provide useful information to researchers involved in this field so that they can have a global vision of the pivotal role played by drug/protein complexes in many areas of biochemistry and pharmacology.

Prof. Dr. Fabrizio Dal Piaz
Prof. Dr. Viviana Izzo
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. Pharmaceutics 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 2900 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

  • protein complexes
  • drug targets
  • mechanism of action
  • drug transport and distribution
  • compound-centered proteomics
  • enzyme activity modulation
  • structural analysis
  • off-targets

Published Papers (7 papers)

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Research

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13 pages, 2260 KiB  
Article
Identification and Relative Quantification of hFSH Glycoforms in Women’s Sera via MS–PRM-Based Approach
by Chiara Melchiorre, Cerina Chhuon, Vincent Jung, Joanna Lipecka, Francesca Di Rella, Alessandro Conforti, Angela Amoresano, Andrea Carpentieri and Ida Chiara Guerrera
Pharmaceutics 2021, 13(6), 798; https://doi.org/10.3390/pharmaceutics13060798 - 27 May 2021
Cited by 1 | Viewed by 2524
Abstract
Follicle-stimulating hormone (FSH) is a glycohormone synthesized by adenohypophysis, and it stimulates ovulation in women and spermatogenesis in men by binding to its receptor (FSHR). FSHR is involved in several mechanisms to transduce intracellular signals in response to the FSH stimulus. Exogenous FSH [...] Read more.
Follicle-stimulating hormone (FSH) is a glycohormone synthesized by adenohypophysis, and it stimulates ovulation in women and spermatogenesis in men by binding to its receptor (FSHR). FSHR is involved in several mechanisms to transduce intracellular signals in response to the FSH stimulus. Exogenous FSH is currently used in the clinic for ovarian hyperstimulation during in vitro fertilization in women, and for treatment of infertility caused by gonadotropin deficiency in men. The glycosylation of FSH strongly affects the binding affinity to its receptor, hence significantly influencing the biological activity of the hormone. Therefore, the accurate measurement and characterization of serum hFSH glycoforms will contribute to elucidating the complex mechanism of action by which different glycoforms elicit distinct biological activity. Nowadays ELISA is the official method with which to monitor serum hFSH, but the test is unable to distinguish between the different FSH glycovariants and is therefore unsuitable to study the biological activity of this hormone. This study presents a preliminary alternative strategy for identifying and quantifying serum hFSH glycoforms based on immunopurification assay and mass spectrometry (MS), and parallel reaction monitoring (PRM) analysis. In this study, we provide an MS–PRM data acquisition method for hFSH glycopeptides identification with high specificity and their quantification by extracting the chromatographic traces of selected fragments of glycopeptides. Once set up for all its features, the proposed method could be transferred to the clinic to improve fertility treatments and follow-ups in men and women. Full article
(This article belongs to the Special Issue Protein–Drug Interaction)
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15 pages, 25047 KiB  
Article
Membrane Environment Modulates Ligand-Binding Propensity of P2Y12 Receptor
by Fatemeh Haghighi, Semen Yesylevskyy, Siamak Davani and Christophe Ramseyer
Pharmaceutics 2021, 13(4), 524; https://doi.org/10.3390/pharmaceutics13040524 - 09 Apr 2021
Cited by 4 | Viewed by 2628
Abstract
The binding of natural ligands and synthetic drugs to the P2Y12 receptor is of great interest because of its crucial role in platelets activation and the therapy of arterial thrombosis. Up to now, all computational studies of P2Y12 concentrated on the available crystal [...] Read more.
The binding of natural ligands and synthetic drugs to the P2Y12 receptor is of great interest because of its crucial role in platelets activation and the therapy of arterial thrombosis. Up to now, all computational studies of P2Y12 concentrated on the available crystal structures, while the role of intrinsic protein dynamics and the membrane environment in the functioning of P2Y12 was not clear. In this work, we performed all-atom molecular dynamics simulations of the full-length P2Y12 receptor in three different membrane environments and in two possible conformations derived from available crystal structures. The binding of ticagrelor, its two major metabolites, adenosine diphosphate (ADP) and 2-Methylthioadenosine diphosphate (2MeS-ADP) as agonist, and ethyl 6-[4-(benzylsulfonylcarbamoyl)piperidin-1-yl]-5-cyano-2-methylpyridine-3-carboxylate (AZD1283)as antagonist were assessed systematically by means of ensemble docking. It is shown that the binding of all ligands becomes systematically stronger with the increase of the membrane rigidity. Binding of all ligands to the agonist-bound-like conformations is systematically stronger in comparison to antagonist-bound-likes ones. This is dramatically opposite to the results obtained for static crystal structures. Our results show that accounting for internal protein dynamics, strongly modulated by its lipid environment, is crucial for correct assessment of the ligand binding to P2Y12. Full article
(This article belongs to the Special Issue Protein–Drug Interaction)
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19 pages, 2865 KiB  
Article
Mechanistic Insights into Side Effects of Troglitazone and Rosiglitazone Using a Novel Inverse Molecular Docking Protocol
by Katarina Kores, Janez Konc and Urban Bren
Pharmaceutics 2021, 13(3), 315; https://doi.org/10.3390/pharmaceutics13030315 - 28 Feb 2021
Cited by 15 | Viewed by 2912
Abstract
Thiazolidinediones form drugs that treat insulin resistance in type 2 diabetes mellitus. Troglitazone represents the first drug from this family, which was removed from use by the FDA due to its hepatotoxicity. As an alternative, rosiglitazone was developed, but it was under the [...] Read more.
Thiazolidinediones form drugs that treat insulin resistance in type 2 diabetes mellitus. Troglitazone represents the first drug from this family, which was removed from use by the FDA due to its hepatotoxicity. As an alternative, rosiglitazone was developed, but it was under the careful watch of FDA for a long time due to suspicion, that it causes cardiovascular diseases, such as heart failure and stroke. We applied a novel inverse molecular docking protocol to discern the potential protein targets of both drugs. Troglitazone and rosiglitazone were docked into predicted binding sites of >67,000 protein structures from the Protein Data Bank and examined. Several new potential protein targets with successfully docked troglitazone and rosiglitazone were identified. The focus was devoted to human proteins so that existing or new potential side effects could be explained or proposed. Certain targets of troglitazone such as 3-oxo-5-beta-steroid 4-dehydrogenase, neutrophil collagenase, stromelysin-1, and VLCAD were pinpointed, which could explain its hepatoxicity, with additional ones indicating that its application could lead to the treatment/development of cancer. Results for rosiglitazone discerned its interaction with members of the matrix metalloproteinase family, which could lead to cancer and neurodegenerative disorders. The concerning cardiovascular side effects of rosiglitazone could also be explained. We firmly believe that our results deepen the mechanistic understanding of the side effects of both drugs, and potentially with further development and research maybe even help to minimize them. On the other hand, the novel inverse molecular docking protocol on the other hand carries the potential to develop into a standard tool to predict possible cross-interactions of drug candidates potentially leading to adverse side effects. Full article
(This article belongs to the Special Issue Protein–Drug Interaction)
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10 pages, 598 KiB  
Article
Target-Mediated Brain Tissue Binding for Small Molecule Inhibitors of Heat Shock Protein 90
by Lassina Badolo, Kenneth Thirstrup, Søren Møller Nielsen, Ask Püschl, Thomas Jensen, Steve Watson and Christoffer Bundgaard
Pharmaceutics 2020, 12(11), 1009; https://doi.org/10.3390/pharmaceutics12111009 - 22 Oct 2020
Cited by 4 | Viewed by 1998
Abstract
Drug distribution in the brain is generally associated with an affinity for fatty brain tissues and therefore known to be species- and concentration-independent. We report here the effect of target affinity on brain tissue binding for 10 small molecules designed to inhibit brain [...] Read more.
Drug distribution in the brain is generally associated with an affinity for fatty brain tissues and therefore known to be species- and concentration-independent. We report here the effect of target affinity on brain tissue binding for 10 small molecules designed to inhibit brain heat shock protein 90 (HSP90), a widespread protein whose expression is 1–2% of total cytosolic proteins in eucaryotes. Our results show that increasing the test item concentrations from 0.3 to 100 µM increased the unbound fraction 32-fold for the most potent molecules, with no change for the inactive one (1.1 fold change). Saturation of HSP90 led to normal concentration-independent brain tissue binding. In vivo pharmacokinetics performed in rats showed that the overall volume of distribution of compounds is correlated with their affinity for HSP90. The in vitro binding and in vivo pharmacokinetics (PK) performed in rats showed that small molecule HSP90 inhibitors followed the principle of target-mediated drug disposition. We demonstrate that assessing unbound fractions in brain homogenate was subject to HSP90 target interference; this may challenge the process of linking systemic-free drug concentrations to central nervous system unbound concentrations necessary to establish the proper pharmacokinetics/pharmacodynamics (PK/PD) relation needed for human dose prediction. Full article
(This article belongs to the Special Issue Protein–Drug Interaction)
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Review

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20 pages, 1413 KiB  
Review
The Effect of Plasma Protein Binding on the Therapeutic Monitoring of Antiseizure Medications
by Bruno Charlier, Albino Coglianese, Federica De Rosa, Ugo de Grazia, Francesca Felicia Operto, Giangennaro Coppola, Amelia Filippelli, Fabrizio Dal Piaz and Viviana Izzo
Pharmaceutics 2021, 13(8), 1208; https://doi.org/10.3390/pharmaceutics13081208 - 05 Aug 2021
Cited by 22 | Viewed by 4696
Abstract
Epilepsy is a widely diffused neurological disorder including a heterogeneous range of syndromes with different aetiology, severity and prognosis. Pharmacological treatments are based on the use, either in mono- or in polytherapy, of antiseizure medications (ASMs), which act at different synaptic levels, generally [...] Read more.
Epilepsy is a widely diffused neurological disorder including a heterogeneous range of syndromes with different aetiology, severity and prognosis. Pharmacological treatments are based on the use, either in mono- or in polytherapy, of antiseizure medications (ASMs), which act at different synaptic levels, generally modifying the excitatory and/or inhibitory response through different action mechanisms. To reduce the risk of adverse effects and drug interactions, ASMs levels should be closely evaluated in biological fluids performing an appropriate Therapeutic Drug Monitoring (TDM). However, many decisions in TDM are based on the determination of the total drug concentration although measurement of the free fraction, which is not bound to plasma proteins, is becoming of ever-increasing importance since it correlates better with pharmacological and toxicological effects. Aim of this work has been to review methodological aspects concerning the evaluation of the free plasmatic fraction of some ASMs, focusing on the effect and the clinical significance that drug-protein binding has in the case of widely used drugs such as valproic acid, phenytoin, perampanel and carbamazepine. Although several validated methodologies are currently available which are effective in separating and quantifying the different forms of a drug, prospective validation studies are undoubtedly needed to better correlate, in real-world clinical contexts, pharmacokinetic monitoring to clinical outcomes. Full article
(This article belongs to the Special Issue Protein–Drug Interaction)
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23 pages, 2981 KiB  
Review
Interactions with Microbial Proteins Driving the Antibacterial Activity of Flavonoids
by Giuliana Donadio, Francesca Mensitieri, Valentina Santoro, Valentina Parisi, Maria Laura Bellone, Nunziatina De Tommasi, Viviana Izzo and Fabrizio Dal Piaz
Pharmaceutics 2021, 13(5), 660; https://doi.org/10.3390/pharmaceutics13050660 - 05 May 2021
Cited by 51 | Viewed by 4152
Abstract
Flavonoids are among the most abundant natural bioactive compounds produced by plants. Many different activities have been reported for these secondary metabolites against numerous cells and systems. One of the most interesting is certainly the antimicrobial, which is stimulated through various molecular mechanisms. [...] Read more.
Flavonoids are among the most abundant natural bioactive compounds produced by plants. Many different activities have been reported for these secondary metabolites against numerous cells and systems. One of the most interesting is certainly the antimicrobial, which is stimulated through various molecular mechanisms. In fact, flavonoids are effective both in directly damaging the envelope of Gram-negative and Gram-positive bacteria but also by acting toward specific molecular targets essential for the survival of these microorganisms. The purpose of this paper is to present an overview of the most interesting results obtained in the research focused on the study of the interactions between flavonoids and bacterial proteins. Despite the great structural heterogeneity of these plant metabolites, it is interesting to observe that many flavonoids affect the same cellular pathways. Furthermore, it is evident that some of these compounds interact with more than one target, producing multiple effects. Taken together, the reported data demonstrate the great potential of flavonoids in developing innovative systems, which can help address the increasingly serious problem of antibiotic resistance. Full article
(This article belongs to the Special Issue Protein–Drug Interaction)
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18 pages, 1154 KiB  
Review
Insights into the Binding of Dietary Phenolic Compounds to Human Serum Albumin and Food-Drug Interactions
by Anallely López-Yerena, Maria Perez, Anna Vallverdú-Queralt and Elvira Escribano-Ferrer
Pharmaceutics 2020, 12(11), 1123; https://doi.org/10.3390/pharmaceutics12111123 - 21 Nov 2020
Cited by 30 | Viewed by 3867
Abstract
The distribution of drugs and dietary phenolic compounds in the systemic circulation de-pends on, among other factors, unspecific/specific reversible binding to plasma proteins such as human serum albumin (HSA). Phenolic substances, present in plant-derived feeds, foods, beverages, herbal medicines, and dietary supplements, are [...] Read more.
The distribution of drugs and dietary phenolic compounds in the systemic circulation de-pends on, among other factors, unspecific/specific reversible binding to plasma proteins such as human serum albumin (HSA). Phenolic substances, present in plant-derived feeds, foods, beverages, herbal medicines, and dietary supplements, are of great interest due to their biological activity. Recently, considerable research has been directed at the formation of phenol–HSA complexes, focusing above all on structure–affinity relationships. The nucleophilicity and planarity of molecules can be altered by the number and position of hydroxyl groups on the aromatic ring and by hydrogenation. Binding affinities towards HSA may also differ between phenolic compounds in their native form and conjugates derived from phase II reactions. On the other hand, food–drug interactions may increase the concentration of free drugs in the blood, affecting their transport and/or disposition and in some cases provoking adverse or toxic effects. This is caused mainly by a decrease in drug binding affinities for HSA in the presence of flavonoids. Accordingly, to avoid the side effects arising from changes in plasma protein binding, the intake of flavonoid-rich food and beverages should be taken into consideration when treating certain pathologies. Full article
(This article belongs to the Special Issue Protein–Drug Interaction)
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