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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 (20 April 2025) | Viewed by 6749

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Special Issue Editors

Dr. Csaba Hetényi

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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
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Dr. Uko Maran

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Institute of Chemistry, University of Tartu, Ravila 14A, 50411 Tartu, Estonia
Interests: theoretical and computer chemistry; malaria drug development
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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 also emerging. 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. Submissions 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

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Published Papers (4 papers)

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Research

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15 pages, 5464 KiB

Open AccessArticle

Acanthopanax Senticosus Saponins Prevent Cognitive Decline in Rats with Alzheimer’s Disease

by Xue-Min Cui, Wang Wang, Lin Yang, Bao-Wen Nie, Qian Liu, Xiao-Hui Li and Dong-Xiao Duan

Int. J. Mol. Sci. 2025, 26(8), 3715; https://doi.org/10.3390/ijms26083715 - 14 Apr 2025

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Abstract

Alzheimer’s disease (AD) is a progressive degenerative disease of the nervous system that affects older adults. Its main clinical manifestations include memory loss, cognitive dysfunction, abnormal behaviour, and social dysfunction. Neuroinflammation is typical in most neurodegenerative diseases, such as AD. Therefore, suppressing inflammation may improve AD symptoms. This study investigated the neuroprotective effects of Acanthopanax senticosus saponins (ASS) in an AD model induced by streptozotocin (STZ). Here, we characterised a rat model of STZ-induced AD with the parallel deterioration of memory loss and neuroinflammation. Following the end of the treatment with ASS (50 mg/kg for 14 consecutive days), behavioural tests (Morris water maze test, Y-maze test) were performed on the rat, and the molecular parameters (DAPK1, Tau5, p-Tau, NF-κB, IL-1β, TNF-α, and NLRP3) of the rat hippocampus were also assessed. We demonstrated that ASS, which has potent anti-inflammatory effects, can reduce neuroinflammation and prevent cognitive impairment. In the water maze test, ASS-treated groups exhibited significantly increased average escape latency (p < 0.05), the percentage of stay in the target quadrant (p < 0.05), and the number of times each group of rats crossed the platform (p < 0.05) compared to the negative control. And ASS could reduce the phosphorylation of the Tau protein (p < 0.001) and death-associated protein kinase 1 (DAPK1, p < 0.001) in the hippocampal tissue, improving cognitive impairment in STZ-treated rats by suppressing the inflammatory response; the molecular analysis showed a significant reduction in pro-inflammatory markers like NLRP3, IL-1β, TNF-α, and NF-κB (p < 0.001). It was also discovered that the NF-κB inhibitor SN50 had the same effect. Therefore, the present study used ASS through its anti-inflammatory effects to prevent and treat AD. This study highlights the potential efficacy of ASS in alleviating cognitive dysfunction in AD. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Proteins in Drug Research)

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22 pages, 6016 KiB

Open AccessArticle

Synthesis, Cytotoxicity, and Mechanistic Evaluation of Tetrahydrocurcumin-Amino Acid Conjugates as LAT1-Targeting Anticancer Agents in C6 Glioma Cells

by Polsak Teerawonganan, Hasriadi, Peththa Wadu Dasuni Wasana, Pornpoom Angsuwattana, Apichart Suksamrarn, Nonthaneth Nalinratana, Opa Vajragupta, Pasarapa Towiwat, Worathat Thitikornpong and Pornchai Rojsitthisak

Int. J. Mol. Sci. 2024, 25(20), 11266; https://doi.org/10.3390/ijms252011266 - 19 Oct 2024

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Abstract

Glioblastoma, a fatal brain cancer with limited treatments and poor prognosis, could benefit from targeting the L-type amino acid transporter I (LAT1). LAT1 is essential for cancer cells to acquire necessary amino acids. Tetrahydrocurcumin (THC), a key curcumin derivative, shows potential for glioblastoma treatment. However, its effectiveness is hindered by poor physicochemical and pharmacokinetic properties. Therefore, this study aims to improve the therapeutic efficacy of THC against glioblastoma by chemically modifying it to target LAT1. A novel series of THC-amino acid conjugates were synthesized by conjugating five amino acids: glycine, leucine, isoleucine, and phenylalanine to THC via carbamate bonds. The therapeutic efficacy of THC-amino acid conjugates was further examined in C6 glioma cells, including the role of LAT1 in their therapeutic effects. Among the conjugates tested, THC conjugated with two phenylalanines (THC-di-Phe) showed remarkably higher cytotoxicity against C6 glioma cells (35.8 μM) compared to THC alone (110.7 μM). THC-di-Phe induced cellular death via necrosis and apoptosis, outperforming THC. Additionally, THC-di-Phe inhibited C6 cell proliferation and migration more effectively than THC. Co-incubation of THC-di-Phe with the LAT1 inhibitor 2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) further increased cellular death. THC-di-Phe also significantly inhibited the P70SK/S6 pathway, regulated by LAT1 inhibitors, more effectively than THC and displayed a similar binding mode with both JX-075 and BCH to the active site of LAT1. Findings suggest the potential role of THC-di-Phe as a LAT1 inhibitor and provide novel insight into its use as a potent antitumor agent in glioma with increased therapeutic efficacy. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Proteins in Drug Research)

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15 pages, 3796 KiB

Open AccessArticle

Synthesis of Estrone Heterodimers and Evaluation of Their In Vitro Antiproliferative Activity

by Noémi Bózsity, Viktória Nagy, Johanna Szabó, Balázs Pálházi, Zoltán Kele, Vivien Resch, Gábor Paragi, István Zupkó, Renáta Minorics and Erzsébet Mernyák

Int. J. Mol. Sci. 2024, 25(8), 4274; https://doi.org/10.3390/ijms25084274 - 12 Apr 2024

Cited by 2 | Viewed by 1562

Abstract

Directed structural modifications of natural products offer excellent opportunities to develop selectively acting drug candidates. Natural product hybrids represent a particular compound group. The components of hybrids constructed from different molecular entities may result in synergic action with diminished side effects. Steroidal homo- or heterodimers deserve special attention owing to their potentially high anticancer effect. Inspired by our recently described antiproliferative core-modified estrone derivatives, here, we combined them into heterodimers via Cu(I)-catalyzed azide–alkyne cycloaddition reactions. The two trans-16-azido-3-(O-benzyl)-17-hydroxy-13α-estrone derivatives were reacted with 3-O-propargyl-D-secoestrone alcohol or oxime. The antiproliferative activities of the four newly synthesized dimers were evaluated against a panel of human adherent gynecological cancer cell lines (cervical: Hela, SiHa, C33A; breast: MCF-7, T47D, MDA-MB-231, MDA-MB-361; ovarian: A2780). One heterodimer (12) exerted substantial antiproliferative activity against all investigated cell lines in the submicromolar or low micromolar range. A pronounced proapoptotic effect was observed by fluorescent double staining and flow cytometry on three cervical cell lines. Additionally, cell cycle blockade in the G2/M phase was detected, which might be a consequence of the effect of the dimer on tubulin polymerization. Computational calculations on the taxoid binding site of tubulin revealed potential binding of both steroidal building blocks, mainly with hydrophobic interactions and water bridges. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Proteins in Drug Research)

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Review

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17 pages, 2680 KiB

Open AccessReview

Computational Characterization of Membrane Proteins as Anticancer Targets: Current Challenges and Opportunities

by Marina Gorostiola González, Pepijn R. J. Rakers, Willem Jespers, Adriaan P. IJzerman, Laura H. Heitman and Gerard J. P. van Westen

Int. J. Mol. Sci. 2024, 25(7), 3698; https://doi.org/10.3390/ijms25073698 - 26 Mar 2024

Cited by 2 | Viewed by 2300

Abstract

Cancer remains a leading cause of mortality worldwide and calls for novel therapeutic targets. Membrane proteins are key players in various cancer types but present unique challenges compared to soluble proteins. The advent of computational drug discovery tools offers a promising approach to address these challenges, allowing for the prioritization of “wet-lab” experiments. In this review, we explore the applications of computational approaches in membrane protein oncological characterization, particularly focusing on three prominent membrane protein families: receptor tyrosine kinases (RTKs), G protein-coupled receptors (GPCRs), and solute carrier proteins (SLCs). We chose these families due to their varying levels of understanding and research data availability, which leads to distinct challenges and opportunities for computational analysis. We discuss the utilization of multi-omics data, machine learning, and structure-based methods to investigate aberrant protein functionalities associated with cancer progression within each family. Moreover, we highlight the importance of considering the broader cellular context and, in particular, cross-talk between proteins. Despite existing challenges, computational tools hold promise in dissecting membrane protein dysregulation in cancer. With advancing computational capabilities and data resources, these tools are poised to play a pivotal role in identifying and prioritizing membrane proteins as personalized anticancer targets. Full article

(This article belongs to the Special Issue Advances in the Molecular Biology of Proteins in Drug Research)

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