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Biomolecules
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Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery
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Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 35570

Special Issue Editors

Dr. Caterina Vicidomini

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Guest Editor
Istituto di Biostrutture e Bioimmagini IBB-CNR, Via Tommaso De Amicis 95, 80145 Naples, Italy
Interests: pharmaceutical chemistry; neurodrugs; protein interactions; spectroscopy; computational chemistry; phytochemistry
Special Issues, Collections and Topics in MDPI journals
Dr. Giovanni N. Roviello

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Guest Editor
Institute of Biostructures and Bioimaging, Italian National Council for Research (IBB-CNR), Via P. Castellino 111, 80131 Naples, Italy
Interests: bioinorganic chemistry; synthetic chemistry; nucleic acid chemistry; spectroscopic studies; computational studies; environmental chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Protein-driven biological processes are of fundamental importance in biomedicine because they are related to pathologies of enormous social relevance, including cancer, neurodegeneration, and viral diseases, like the current COVID-19 pandemic. In this Special Issue, we wish to focus on the novel experimental and theoretical approaches for drug discovery, design, and development, with a particular attention being paid to the mechanisms of drug interference with protein-driven biological pathways. However, contributions on nucleic acid–protein interaction, peptide aggregation, nucleopeptide chemistry, and antimicrobial polyamino acids are also welcome, as they could improve overall knowledge on the amino acid-based biochemistry at the interface between drug design and therapy. Other themes of interest are inherent to the computational chemistry applied to protein and peptide science.

This Special Issue is open to the submission of both original articles and reviews that describe research and ideas on themes treated in this issue for protein-based molecular strategies.

Dr. Giovanni N. Roviello
Dr. Caterina Vicidomini
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. 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

  • proteins
  • peptides
  • amyloid
  • Alzheimer disease
  • Parkinson’s disease
  • Neurodrugs
  • Biotechnological enzymes
  • antiviral drugs
  • vaccines
  • biomolecular targets
  • COVID-19
  • SARS-CoV-2
  • Spike Protein
  • Peptide aggregation
  • Drug Repurposing
  • Natural products
  • Synthetic antivirals
  • Anticancer therapeutics

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Related Special Issue

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

4 pages, 746 KiB  
Editorial
Protein-Targeting Drug Discovery
by Caterina Vicidomini and Giovanni N. Roviello
Biomolecules 2023, 13(11), 1591; https://doi.org/10.3390/biom13111591 - 29 Oct 2023
Cited by 1 | Viewed by 1759
Abstract
Protein-driven biological processes play a fundamental role in biomedicine because they are related to pathologies of enormous social impact, such as cancer, neuropathies, and viral diseases, including the one at the origin of the recent COVID-19 pandemic [...] Full article
(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)
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Research

Jump to: Editorial, Review

12 pages, 2811 KiB  
Communication
Analysis of Different Binding Modes for Tiagabine within the GAT-1 Transporter
by Kamil Łątka and Marek Bajda
Biomolecules 2022, 12(11), 1663; https://doi.org/10.3390/biom12111663 - 9 Nov 2022
Cited by 4 | Viewed by 2049
Abstract
The recently obtained cryo-electron microscopy structure (PDB code: 7SK2) of the human γ-aminobutyric acid transporter type 1 (hGAT-1) in complex with the antiepileptic drug, tiagabine, revealed a rather unexpected binding mode for this inhibitor in an inward-open state of the transporter. The simultaneously [...] Read more.
The recently obtained cryo-electron microscopy structure (PDB code: 7SK2) of the human γ-aminobutyric acid transporter type 1 (hGAT-1) in complex with the antiepileptic drug, tiagabine, revealed a rather unexpected binding mode for this inhibitor in an inward-open state of the transporter. The simultaneously released crystal structures of the modified dopamine transporter with mutations mimicking hGAT-1 indicated an alternative binding mode for the tiagabine analogues that were found to block the transporter in an outward-open state, which is more consistent with the results of previous biological and molecular modeling studies. In view of the above discrepancies, our study compares different hypothetical tiagabine binding modes using classical and accelerated molecular dynamics simulations, as well as MM-GBSA free binding energy (dG) calculations. The results indicate that the most stable and energetically favorable binding mode of tiagabine is the one where the nipecotic acid fragment is located in the main binding site (S1) and the aromatic rings are arranged within the S2 site of the hGAT-1 transporter in an outward-open state, confirming the previous molecular modelling findings. The position of tiagabine bound to hGAT-1 in an inward-open state, partially within the intracellular release pathway, was significantly less stable and the dG values calculated for this complex were higher. Furthermore, analysis of the cryo-electron map for the 7SK2 structure shows that the model does not appear to fit into the map optimally at the ligand binding site. These findings suggest that the position of tiagabine found in the 7SK2 structure is rather ambiguous and requires further experimental verification. The identification of the main, high-affinity binding site for tiagabine and its analogues is crucial for the future rational design of the GABA transporter inhibitors. Full article
(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)
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14 pages, 3087 KiB  
Article
Plasmodium falciparum Nicotinamidase as A Novel Antimalarial Target
by Dickson Donu, Chiranjeev Sharma and Yana Cen
Biomolecules 2022, 12(8), 1109; https://doi.org/10.3390/biom12081109 - 12 Aug 2022
Viewed by 2176
Abstract
Inhibition of Plasmodium falciparum nicotinamidase could represent a potential antimalarial since parasites require nicotinic acid to successfully recycle nicotinamide to NAD+, and importantly, humans lack this biosynthetic enzyme. Recently, mechanism-based inhibitors of nicotinamidase have been discovered. The most potent compound inhibits [...] Read more.
Inhibition of Plasmodium falciparum nicotinamidase could represent a potential antimalarial since parasites require nicotinic acid to successfully recycle nicotinamide to NAD+, and importantly, humans lack this biosynthetic enzyme. Recently, mechanism-based inhibitors of nicotinamidase have been discovered. The most potent compound inhibits both recombinant P. falciparum nicotinamidase and parasites replication in infected human red blood cells (RBCs). These studies provide evidence for the importance of nicotinamide salvage through nicotinamidase as a central master player of NAD+ homeostasis in P. falciparum. Full article
(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)
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18 pages, 8529 KiB  
Article
CD, UV, and In Silico Insights on the Effect of 1,3-Bis(1′-uracilyl)-2-propanone on Serum Albumin Structure
by Francesca Greco, Andrea Patrizia Falanga, Monica Terracciano, Carlotta D’Ambrosio, Gennaro Piccialli, Giorgia Oliviero, Giovanni Nicola Roviello and Nicola Borbone
Biomolecules 2022, 12(8), 1071; https://doi.org/10.3390/biom12081071 - 3 Aug 2022
Cited by 9 | Viewed by 2296
Abstract
1,3-diaryl-2-propanone derivatives are synthetic compounds used as building blocks for the realization not only of antimicrobial drugs but also of new nanomaterials thanks to their ability to self-assemble in solution and interact with nucleopeptides. However, their ability to interact with proteins is a [...] Read more.
1,3-diaryl-2-propanone derivatives are synthetic compounds used as building blocks for the realization not only of antimicrobial drugs but also of new nanomaterials thanks to their ability to self-assemble in solution and interact with nucleopeptides. However, their ability to interact with proteins is a scarcely investigated theme considering the therapeutic importance that 1,3-diaryl-2-propanones could have in the modulation of protein-driven processes. Within this scope, we investigated the protein binding ability of 1,3-bis(1′-uracilyl)-2-propanone, which was previously synthesized in our laboratory utilizing a Dakin–West reaction and herein indicated as U2O, using bovine serum albumin (BSA) as the model protein. Through circular dichroism (CD) and UV spectroscopy, we demonstrated that the compound, but not the similar thymine derivative T2O, was able to alter the secondary structure of the serum albumin leading to significant consequences in terms of BSA structure with respect to the unbound protein (Δβ-turn + Δβ-sheet = +23.6%, Δα = −16.7%) as revealed in our CD binding studies. Moreover, molecular docking studies suggested that U2O is preferentially housed in the domain IIIB of the protein, and its affinity for the albumin is higher than that of the reference ligand HA 14−1 (HDOCK score (top 1–3 poses): −157.11 ± 1.38 (U2O); −129.80 ± 6.92 (HA 14−1); binding energy: −7.6 kcal/mol (U2O); −5.9 kcal/mol (HA 14−1)) and T2O (HDOCK score (top 1–3 poses): −149.93 ± 2.35; binding energy: −7.0 kcal/mol). Overall, the above findings suggest the ability of 1,3-bis(1′-uracilyl)-2-propanone to bind serum albumins and the observed reduction of the α-helix structure with the concomitant increase in the β-structure are consistent with a partial protein destabilization due to the interaction with U2O. Full article
(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)
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12 pages, 2449 KiB  
Article
Protein Binding of Benzofuran Derivatives: A CD Spectroscopic and In Silico Comparative Study of the Effects of 4-Nitrophenyl Functionalized Benzofurans and Benzodifurans on BSA Protein Structure
by Pasqualina Liana Scognamiglio, Caterina Vicidomini, Francesco Fontanella, Claudio De Stefano, Rosanna Palumbo and Giovanni N. Roviello
Biomolecules 2022, 12(2), 262; https://doi.org/10.3390/biom12020262 - 5 Feb 2022
Cited by 7 | Viewed by 2553
Abstract
Benzofuran derivatives are synthetic compounds that are finding an increasing interest in the scientific community not only as building blocks for the realization of new materials, but also as potential drugs thanks to their ability to interact with nucleic acids, interfere with the [...] Read more.
Benzofuran derivatives are synthetic compounds that are finding an increasing interest in the scientific community not only as building blocks for the realization of new materials, but also as potential drugs thanks to their ability to interact with nucleic acids, interfere with the amyloid peptide aggregation and cancer cell cycle. However, their ability to interact with proteins is a theme still in need of investigation for the therapeutic importance that benzofurans could have in the modulation of protein-driven processes and for the possibility of making use of serum albumins as benzofurans delivery systems. To this scope, we investigated the protein binding ability of two 4-nitrophenyl-functionalized benzofurans previously synthesized in our laboratory and herein indicated as BF1 and BDF1, which differed for the number of furan rings (a single moiety in BF1, two in BDF1), using bovine serum albumin (BSA) as a model protein. By circular dichroism (CD) spectroscopy we demonstrated the ability of the two heteroaromatic compounds to alter the secondary structure of the serum albumin leading to different consequences in terms of BSA thermal stability with respect to the unbound protein (ΔTm > 3 °C for BF1, −0.8 °C for BDF1 with respect to unbound BSA, in PBS buffer, pH 7.5) as revealed in our CD melting studies. Moreover, a molecular docking study allowed us to compare the possible ligand binding modes of the mono and difuranic derivatives showing that while BF1 is preferentially housed in the interior of protein structure, BDF1 is predicted to bind the albumin surface with a lower affinity than BF1. Interestingly, the different affinity for the protein target predicted computationally was confirmed also experimentally by fluorescence spectroscopy (kD = 142.4 ± 64.6 nM for BDF1 vs. 28.4 ± 10.1 nM for BF1). Overall, the above findings suggest the ability of benzofurans to bind serum albumins that could act as their carriers in drug delivery applications. Full article
(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)
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19 pages, 5855 KiB  
Article
Synthesis and Spectroscopic Investigations of Schiff Base Ligand and Its Bimetallic Ag(I) Complex as DNA and BSA Binders
by Martyna Szymańska, Izabela Pospieszna-Markiewicz, Martyna Mańka, Małgorzata Insińska-Rak, Grzegorz Dutkiewicz, Violetta Patroniak and Marta A. Fik-Jaskółka
Biomolecules 2021, 11(10), 1449; https://doi.org/10.3390/biom11101449 - 2 Oct 2021
Cited by 17 | Viewed by 3293
Abstract
Generation of well-defined potential metallotherapeutics for cancer treatment, one of the most population-threatening diseases, is challenging and an active area of modern research in view of their unique properties and thus multiple possible pathways of action in cells. Specifically, Schiff base ligands were [...] Read more.
Generation of well-defined potential metallotherapeutics for cancer treatment, one of the most population-threatening diseases, is challenging and an active area of modern research in view of their unique properties and thus multiple possible pathways of action in cells. Specifically, Schiff base ligands were recognized as very promising building blocks for the construction of stable and active complexes of numerous geometries and topologies. Incorporation of Ag(I) ions allows for the formation of flat complexes with potential unoccupied coordination sites, thus giving rise to specific interactions between the metallotherapeutic and biomolecule of interest. Herein, we present the design, synthesis and characterization of new Schiff base ligand L and its Ag(I) bimetallic complex [Ag2L2]2+ with two planar moieties formed around the metal ions and connected through cyclohexane rings, confirmed by X-ray measurements. The compounds were described in context of their potential use as anticancer drugs through DNA and BSA binding pathways by several spectroscopic methods (CD, UV-Vis, fluorescence). We revealed that both, L and [Ag2L2]2+, interact with similar affinity with CT-DNA (Kb~106 M−1), while they differ in the type and strength of interactions with the model albumin–BSA. [Ag2L2]2+ binds BSA in both a dynamic and static manner with the Ksv = 8.8 × 104 M−1 in the Trp-134 and Trp-213 sites, whereas L interacts with BSA only dynamically (KSV = 2.4 × 104 M−1). This found further confirmation in the CD studies which revealed a reduction in α-helix content in the albumin of 16% in presence of [Ag2L2]2+. Full article
(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)
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17 pages, 22198 KiB  
Article
Interference of Polydatin/Resveratrol in the ACE2:Spike Recognition during COVID-19 Infection. A Focus on Their Potential Mechanism of Action through Computational and Biochemical Assays
by Fulvio Perrella, Federico Coppola, Alessio Petrone, Chiara Platella, Daniela Montesarchio, Annarita Stringaro, Giampietro Ravagnan, Maria Pia Fuggetta, Nadia Rega and Domenica Musumeci
Biomolecules 2021, 11(7), 1048; https://doi.org/10.3390/biom11071048 - 16 Jul 2021
Cited by 25 | Viewed by 5102
Abstract
In the search for new therapeutic strategies to contrast SARS-CoV-2, we here studied the interaction of polydatin (PD) and resveratrol (RESV)—two natural stilbene polyphenols with manifold, well known biological activities—with Spike, the viral protein essential for virus entry into host cells, and ACE2, [...] Read more.
In the search for new therapeutic strategies to contrast SARS-CoV-2, we here studied the interaction of polydatin (PD) and resveratrol (RESV)—two natural stilbene polyphenols with manifold, well known biological activities—with Spike, the viral protein essential for virus entry into host cells, and ACE2, the angiotensin-converting enzyme present on the surface of multiple cell types (including respiratory epithelial cells) which is the main host receptor for Spike binding. Molecular Docking simulations evidenced that both compounds can bind Spike, ACE2 and the ACE2:Spike complex with good affinity, although the interaction of PD appears stronger than that of RESV on all the investigated targets. Preliminary biochemical assays revealed a significant inhibitory activity of the ACE2:Spike recognition with a dose-response effect only in the case of PD. Full article
(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)
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Review

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32 pages, 9181 KiB  
Review
Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present
by Sarah E. Huff, Jordan M. Winter and Chris G. Dealwis
Biomolecules 2022, 12(6), 815; https://doi.org/10.3390/biom12060815 - 10 Jun 2022
Cited by 20 | Viewed by 5179
Abstract
Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR [...] Read more.
Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR has long been considered an attractive drug target for a range of proliferative diseases, including cancer. While there are many excellent reviews regarding the structure, function, and clinical importance of hRR, recent years have seen an increase in novel approaches to inhibiting hRR that merit an updated discussion of the existing inhibitors and strategies to target this enzyme. In this review, we discuss the mechanisms and clinical applications of classic nucleoside analog inhibitors of hRRM1 (large catalytic subunit), including gemcitabine and clofarabine, as well as inhibitors of the hRRM2 (free radical housing small subunit), including triapine and hydroxyurea. Additionally, we discuss novel approaches to targeting RR and the discovery of new classes of hRR inhibitors. Full article
(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)
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23 pages, 1190 KiB  
Review
ADP-Ribosylation Post-Translational Modification: An Overview with a Focus on RNA Biology and New Pharmacological Perspectives
by Giuseppe Manco, Giuseppina Lacerra, Elena Porzio and Giuliana Catara
Biomolecules 2022, 12(3), 443; https://doi.org/10.3390/biom12030443 - 13 Mar 2022
Cited by 10 | Viewed by 4145
Abstract
Cellular functions are regulated through the gene expression program by the transcription of new messenger RNAs (mRNAs), alternative RNA splicing, and protein synthesis. To this end, the post-translational modifications (PTMs) of proteins add another layer of complexity, creating a continuously fine-tuned regulatory network. [...] Read more.
Cellular functions are regulated through the gene expression program by the transcription of new messenger RNAs (mRNAs), alternative RNA splicing, and protein synthesis. To this end, the post-translational modifications (PTMs) of proteins add another layer of complexity, creating a continuously fine-tuned regulatory network. ADP-ribosylation (ADPr) is an ancient reversible modification of cellular macromolecules, regulating a multitude of key functional processes as diverse as DNA damage repair (DDR), transcriptional regulation, intracellular transport, immune and stress responses, and cell survival. Additionally, due to the emerging role of ADP-ribosylation in pathological processes, ADP-ribosyltransferases (ARTs), the enzymes involved in ADPr, are attracting growing interest as new drug targets. In this review, an overview of human ARTs and their related biological functions is provided, mainly focusing on the regulation of ADP-ribosyltransferase Diphtheria toxin-like enzymes (ARTD)-dependent RNA functions. Finally, in order to unravel novel gene functional relationships, we propose the analysis of an inventory of human gene clusters, including ARTDs, which share conserved sequences at 3′ untranslated regions (UTRs). Full article
(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)
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25 pages, 3300 KiB  
Review
Therapeutic Approaches Targeting Proteins in Tumor-Associated Macrophages and Their Applications in Cancers
by Deyang Wu, Xiaowei Liu, Jingtian Mu, Jin Yang, Fanglong Wu and Hongmei Zhou
Biomolecules 2022, 12(3), 392; https://doi.org/10.3390/biom12030392 - 2 Mar 2022
Cited by 12 | Viewed by 4877
Abstract
Tumor-associated macrophages (TAMs) promote tumor proliferation, invasion, angiogenesis, stemness, therapeutic resistance, and immune tolerance in a protein-dependent manner. Therefore, the traditional target paradigms are often insufficient to exterminate tumor cells. These pro-tumoral functions are mediated by the subsets of macrophages that exhibit canonical [...] Read more.
Tumor-associated macrophages (TAMs) promote tumor proliferation, invasion, angiogenesis, stemness, therapeutic resistance, and immune tolerance in a protein-dependent manner. Therefore, the traditional target paradigms are often insufficient to exterminate tumor cells. These pro-tumoral functions are mediated by the subsets of macrophages that exhibit canonical protein markers, while simultaneously having unique transcriptional features, which makes the proteins expressed on TAMs promising targets during anti-tumor therapy. Herein, TAM-associated protein-dependent target strategies were developed with the aim of either reducing the numbers of TAMs or inhibiting the pro-tumoral functions of TAMs. Furthermore, the recent advances in TAMs associated with tumor metabolism and immunity were extensively exploited to repolarize these TAMs to become anti-tumor elements and reverse the immunosuppressive tumor microenvironment. In this review, we systematically summarize these current studies to fully illustrate the TAM-associated protein targets and their inhibitors, and we highlight the potential clinical applications of targeting the crosstalk among TAMs, tumor cells, and immune cells in anti-tumor therapy. Full article
(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)
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