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Biomedicines
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Protein–Ligand Interactions: Target Identification and Drug Discovery 2.0
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Protein–Ligand Interactions: Target Identification and Drug Discovery 2.0

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: closed (30 April 2023) | Viewed by 16156

Special Issue Editor

Prof. Dr. Fabio Altieri

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Guest Editor
Department of Biochemical Sciences “A. RossiFanelli”, La Sapienza University, 00185 Rome, Italy
Interests: oxidative stress; cellular biochemistry; signal transduction; protein–ligand interaction; bioactive compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Bioactive compounds and drugs are designed and screened on the basis of specific molecular targets as well as the identification of active ingredients from traditional medicine or by serendipitous discovery. The development of novel therapeutic strategies requires a deep knowledge of not only the molecular processes and the cellular pathways involved in each pathological condition and disease, but also the specific protein targets and the effects of drug binding on protein conformation and activity. The understanding of how drugs can modify and modulate specific cellular pathways and functions will be helpful during the process of drug development and clinical trials.

For many bioactive compounds, there is a lack of knowledge of the specific molecular targets involved, the effects of these substances on protein structure, and how they can modulate different cellular pathways and functions. This Special Issue focuses on recent studies aiming to investigate protein–ligand interactions with a special aim of elucidating the molecular modes of action of drugs as well as natural bioactive compounds. Studies highlighting information on target proteins and how interactions with a drug may affect a protein’s structure and biological activity will be welcome. Computational results accompanied by validation experiments are also sought after. This information will help to elucidate the molecular basis for many drugs’ activities and the development of new drugs.

Prof. Dr. Fabio Altieri
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. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

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Related Special Issues

Published Papers (5 papers)

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Research

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15 pages, 3855 KiB  
Article
Unraveling the Mechanism of Epichaperome Modulation by Zelavespib: Biochemical Insights on Target Occupancy and Extended Residence Time at the Site of Action
by Sahil Sharma, Suhasini Joshi, Teja Kalidindi, Chander S. Digwal, Palak Panchal, Sang-Gyu Lee, Pat Zanzonico, Nagavarakishore Pillarsetty and Gabriela Chiosis
Biomedicines 2023, 11(10), 2599; https://doi.org/10.3390/biomedicines11102599 - 22 Sep 2023
Cited by 4 | Viewed by 3139
Abstract
Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome [...] Read more.
Drugs with a long residence time at their target sites are often more efficacious in disease treatment. The mechanism, however, behind prolonged retention at the site of action is often difficult to understand for non-covalent agents. In this context, we focus on epichaperome agents, such as zelavespib and icapamespib, which maintain target binding for days despite rapid plasma clearance, minimal retention in non-diseased tissues, and rapid metabolism. They have shown significant therapeutic value in cancer and neurodegenerative diseases by disassembling epichaperomes, which are assemblies of tightly bound chaperones and other factors that serve as scaffolding platforms to pathologically rewire protein–protein interactions. To investigate their impact on epichaperomes in vivo, we conducted pharmacokinetic and target occupancy measurements for zelavespib and monitored epichaperome assemblies biochemically in a mouse model. Our findings provide evidence of the intricate mechanism through which zelavespib modulates epichaperomes in vivo. Initially, zelavespib becomes trapped when epichaperomes bound, a mechanism that results in epichaperome disassembly, with no change in the expression level of epichaperome constituents. We propose that the initial trapping stage of epichaperomes is a main contributing factor to the extended on-target residence time observed for this agent in clinical settings. Zelavespib’s residence time in tumors seems to be dictated by target disassembly kinetics rather than by frank drug–target unbinding kinetics. The off-rate of zelavespib from epichaperomes is, therefore, much slower than anticipated from the recorded tumor pharmacokinetic profile or as determined in vitro using diluted systems. This research sheds light on the underlying processes that make epichaperome agents effective in the treatment of certain diseases. Full article
(This article belongs to the Special Issue Protein–Ligand Interactions: Target Identification and Drug Discovery 2.0)
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14 pages, 5723 KiB  
Article
Evaluation of Cx43 Gap Junction Inhibitors Using a Quantitative Structure-Activity Relationship Model
by Ramona Matusevičiūtė, Eglė Ignatavičiūtė, Rokas Mickus, Sergio Bordel, Vytenis Arvydas Skeberdis and Vytautas Raškevičius
Biomedicines 2023, 11(7), 1972; https://doi.org/10.3390/biomedicines11071972 - 12 Jul 2023
Cited by 1 | Viewed by 1434
Abstract
Gap junctions (GJs) made of connexin-43 (Cx43) are necessary for the conduction of electrical impulses in the heart. Modulation of Cx43 GJ activity may be beneficial in the treatment of cardiac arrhythmias and other dysfunctions. The search for novel GJ-modulating agents using molecular [...] Read more.
Gap junctions (GJs) made of connexin-43 (Cx43) are necessary for the conduction of electrical impulses in the heart. Modulation of Cx43 GJ activity may be beneficial in the treatment of cardiac arrhythmias and other dysfunctions. The search for novel GJ-modulating agents using molecular docking allows for the accurate prediction of binding affinities of ligands, which, unfortunately, often poorly correlate with their potencies. The objective of this study was to demonstrate that a Quantitative Structure-Activity Relationship (QSAR) model could be used for more precise identification of potent Cx43 GJ inhibitors. Using molecular docking, QSAR, and 3D-QSAR, we evaluated 16 known Cx43 GJ inhibitors, suggested the monocyclic monoterpene d-limonene as a putative Cx43 inhibitor, and tested it experimentally in HeLa cells expressing exogenous Cx43. The predicted concentrations required to produce 50% of the maximal effect (IC50) for each of these compounds were compared with those determined experimentally (pIC50 and eIC50, respectively). The pIC50ies of d-limonene and other Cx43 GJ inhibitors examined by our QSAR and 3D-QSAR models showed a good correlation with their eIC50ies (R = 0.88 and 0.90, respectively) in contrast to pIC50ies obtained from molecular docking (R = 0.78). However, molecular docking suggests that inhibitor potency may depend on their docking conformation on Cx43. Searching for new potent, selective, and specific inhibitors of GJ channels, we propose to perform the primary screening of new putative compounds using the QSAR model, followed by the validation of the most suitable candidates by patch-clamp techniques. Full article
(This article belongs to the Special Issue Protein–Ligand Interactions: Target Identification and Drug Discovery 2.0)
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22 pages, 6586 KiB  
Article
Identification of NSP3 (SH2D3C) as a Prognostic Biomarker of Tumor Progression and Immune Evasion for Lung Cancer and Evaluation of Organosulfur Compounds from Allium sativum L. as Therapeutic Candidates
by Yuan-Chieh Yeh, Bashir Lawal, Michael Hsiao, Tse-Hung Huang and Chi-Ying F. Huang
Biomedicines 2021, 9(11), 1582; https://doi.org/10.3390/biomedicines9111582 - 30 Oct 2021
Cited by 14 | Viewed by 3041
Abstract
The multi-domain non-structural protein 3 (NSP3) is an oncogenic molecule that has been concomitantly implicated in the progression of coronavirus infection. However, its oncological role in lung cancer and whether it plays a role in modulating the tumor immune microenvironment is [...] Read more.
The multi-domain non-structural protein 3 (NSP3) is an oncogenic molecule that has been concomitantly implicated in the progression of coronavirus infection. However, its oncological role in lung cancer and whether it plays a role in modulating the tumor immune microenvironment is not properly understood. In the present in silico study, we demonstrated that NSP3 (SH2D3C) is associated with advanced stage and poor prognoses of lung cancer cohorts. Genetic alterations of NSP3 (SH2D3C) co-occurred inversely with Epidermal Growth Factor Receptor (EGFR) alterations and elicited its pathological role via modulation of various components of the immune and inflammatory pathways in lung cancer. Our correlation analysis suggested that NSP3 (SH2D3C) promotes tumor immune evasion via dysfunctional T-cell phenotypes and T-cell exclusion mechanisms in lung cancer patients. NSP3 (SH2D3C) demonstrated a high predictive value and association with therapy resistance in lung cancer, hence serving as an attractive target for therapy exploration. We evaluated the in silico drug-likeness and NSP3 (SH2D3C) target efficacy of six organosulfur small molecules from Allium sativum using a molecular docking study. We found that the six organosulfur compounds demonstrated selective cytotoxic potential against cancer cell lines and good predictions for ADMET properties, drug-likeness, and safety profile. E-ajoene, alliin, diallyl sulfide, 2-vinyl-4H-1,3-dithiin, allicin, and S-allyl-cysteine docked well into the NSP3 (SH2D3C)-binding cavity with binding affinities ranging from –4.3~–6.70 Ă and random forest (RF) scores ranging from 4.31~5.26 pKd. However, S-allyl-cysteine interaction with NSP3 (SH2D3C) is unfavorable and hence less susceptible to NSP3 ligandability. In conclusion, our study revealed that NSP3 is an important onco-immunological biomarker encompassing the tumor microenvironment, disease staging and prognosis in lung cancer and could serve as an attractive target for cancer therapy. The organosulfur compounds from A. sativum have molecular properties to efficiently interact with the binding site of NSP3 and are currently under vigorous preclinical study in our laboratory. Full article
(This article belongs to the Special Issue Protein–Ligand Interactions: Target Identification and Drug Discovery 2.0)
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18 pages, 3374 KiB  
Article
A Comparative Analysis of Punicalagin Interaction with PDIA1 and PDIA3 by Biochemical and Computational Approaches
by Giuliano Paglia, Lorenzo Antonini, Laura Cervoni, Rino Ragno, Manuela Sabatino, Marco Minacori, Elisabetta Rubini and Fabio Altieri
Biomedicines 2021, 9(11), 1533; https://doi.org/10.3390/biomedicines9111533 - 25 Oct 2021
Cited by 6 | Viewed by 2453
Abstract
In a previous work, it was shown that punicalagin, an active ingredient of pomegranate, is able to bind to PDIA3 and inhibit its disulfide reductase activity. Here we provide evidence that punicalagin can also bind to PDIA1, the main expressed form of protein [...] Read more.
In a previous work, it was shown that punicalagin, an active ingredient of pomegranate, is able to bind to PDIA3 and inhibit its disulfide reductase activity. Here we provide evidence that punicalagin can also bind to PDIA1, the main expressed form of protein disulfide isomerase (PDI). In this comparative study, the affinity and the effect of punicalagin binding on each protein were evaluated, and a computational approach was used to identify putative binding sites. Punicalagin binds to either PDIA1 or PDIA3 with a similar affinity, but the inhibition efficacy on protein reductase activity is higher for PDIA3. Additionally, punicalagin differently affects the thermal denaturation profile of both proteins. Molecular docking and molecular dynamics simulations led to propose a punicalagin binding mode on PDIA1 and PDIA3, identifying the binding sites at the redox domains a’ in two different pockets, suggesting different effects of punicalagin on proteins’ structure. This study provides insights to develop punicalagin-based ligands, to set up a rational design for PDIA3 selective inhibitors, and to dissect the molecular determinant to modulate the protein activity. Full article
(This article belongs to the Special Issue Protein–Ligand Interactions: Target Identification and Drug Discovery 2.0)
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Review

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28 pages, 6366 KiB  
Review
Impact of Protein Corona on the Biological Identity of Nanomedicine: Understanding the Fate of Nanomaterials in the Biological Milieu
by Md Habban Akhter, Habibullah Khalilullah, Manish Gupta, Mohamed A. Alfaleh, Nabil A. Alhakamy, Yassine Riadi and Shadab Md
Biomedicines 2021, 9(10), 1496; https://doi.org/10.3390/biomedicines9101496 - 19 Oct 2021
Cited by 39 | Viewed by 4380
Abstract
Nanoparticles (NPs) in contact with a biological medium are rapidly comprehended by a number of protein molecules resulting in the formation of an NP–protein complex called protein corona (PC). The cell sees the protein-coated NPs as the synthetic identity is masked by protein [...] Read more.
Nanoparticles (NPs) in contact with a biological medium are rapidly comprehended by a number of protein molecules resulting in the formation of an NP–protein complex called protein corona (PC). The cell sees the protein-coated NPs as the synthetic identity is masked by protein surfacing. The PC formation ultimately has a substantial impact on various biological processes including drug release, drug targeting, cell recognition, biodistribution, cellular uptake, and therapeutic efficacy. Further, the composition of PC is largely influenced by the physico-chemical properties of NPs viz. the size, shape, surface charge, and surface chemistry in the biological milieu. However, the change in the biological responses of the new substrate depends on the quantity of protein access by the NPs. The PC-layered NPs act as new biological entities and are recognized as different targeting agents for the receptor-mediated ingress of therapeutics in the biological cells. The corona-enveloped NPs have both pros and cons in the biological system. The review provides a brief insight into the impact of biomolecules on nanomaterials carrying cargos and their ultimate fate in the biological milieu. Full article
(This article belongs to the Special Issue Protein–Ligand Interactions: Target Identification and Drug Discovery 2.0)
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