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Protein–Ligand Interactions: Deciphering the Molecular Targets and the Mechanisms of Action of Drugs and Natural Compounds

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

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 37382

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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,

Drug discovery is a process where bioactive compounds are designed and screened either on the basis of specific molecular targets or by the identification of active ingredients from traditional medicine, as well as by serendipitous discovery. Both forward and reverse pharmacology approaches not only require a deep knowledge of the molecular processes involved in each pathological condition and disease but also the specific protein targets and the effects of drug binding on the conformation and activity of the proteins involved. An 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.

This Special Issue focuses on recent studies that aimed to investigate protein–ligand interactions, with a special aim to elucidate the molecular mode of action and the protein targets of drugs as well as natural compounds, and the cellular pathways involved. Indeed, protein–ligand interactions may affect both protein conformation and biological activity. However, for many bioactive compounds there is a lack of knowledge of their molecular targets, their effects on protein structure, and how they can modulate different cellular pathways and functions. Studies providing such information are welcomed and will help to elucidate the molecular basis for many drugs activity 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. 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

protein-ligand interaction
molecular mode of actions
target identification
drug discovery
bioactive agents

Published Papers (9 papers)

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Research

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24 pages, 6157 KiB

Open AccessArticle

Fli-1 Activation through Targeted Promoter Activity Regulation Using a Novel 3’, 5’-diprenylated Chalcone Inhibits Growth and Metastasis of Prostate Cancer Cells

by Youfen Ma, Bixue Xu, Jia Yu, Lirong Huang, Xiaoping Zeng, Xiangchun Shen, Chunyan Ren, Yaacov Ben-David and Heng Luo

Int. J. Mol. Sci. 2020, 21(6), 2216; https://doi.org/10.3390/ijms21062216 - 23 Mar 2020

Cited by 16 | Viewed by 3481

Abstract

The friend leukemia integration 1 (Fli-1) gene is involved in the expression control of key genes in multiple pathogenic/physiological processes, including cell growth, differentiation, and apoptosis; this implies that Fli-1 is a strong candidate for drug development. In our previous study, a 3′,5′-diprenylated chalcone, (E)-1-(2-hydroxy-4-methoxy-3,5-diprenyl) phenyl-3-(3-pyridinyl)-propene-1-one (C10), was identified as a novel anti-prostate cancer (PCa) agent. Here, we investigated the molecular mechanisms underlying the anti-cancer effects of C10 on the growth, metastasis, and invasion of PC3 cells in vitro. Our results show that C10 exhibited a strong inhibitory effect on proliferation and metastasis of PC3 cells via several cellular and flow cytometric analyses. Further mechanism studies revealed that C10 likely serves as an Fli-1 agonist for regulating the expression of Fli-1 target genes including phosphatidylinositol 3-kinase (P110), murine double minute2 (MDM2), B-cell lymphoma-2 (Bcl-2), Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP-1), and globin transcription factor-1 (Gata-1) as well as the phosphorylation of extracellular-regulated protein kinases 1 (ERK1). Further, we confirmed that C10 can regulate the expressions of vascular endothelial growth factor 1 (VEGF-1), transforming growth factor-β2 (TGF-β2), intercellular cell adhesion molecule-1 (ICAM-1), p53, and matrix metalloproteinase 1 (MMP-1) genes associated with tumor apoptosis, migration, and invasion. Thus, C10 exhibits stronger anticancer activity with novel molecular targets and regulatory molecular mechanisms, indicating its great potency for development as a novel targeted anticancer drug. Full article

(This article belongs to the Special Issue Protein–Ligand Interactions: Deciphering the Molecular Targets and the Mechanisms of Action of Drugs and Natural Compounds)

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18 pages, 3760 KiB

Open AccessArticle

Mechanisms of Action of Cassiae Semen for Weight Management: A Computational Molecular Docking Study of Serotonin Receptor 5-HT2C

by Heidi Yuen, Andrew Hung, Angela Wei Hong Yang and George Binh Lenon

Int. J. Mol. Sci. 2020, 21(4), 1326; https://doi.org/10.3390/ijms21041326 - 16 Feb 2020

Cited by 9 | Viewed by 3673

Abstract

Overweight and obesity is a growing global health concern. Current management of obesity includes lifestyle intervention, bariatric surgery and medication. The serotonin receptor, 5-HT2C, is known to mediate satiety, appetite and consumption behaviour. Lorcaserin, an appetite control drug, has demonstrated efficacy in appetite control by targeting 5-HT2C but causes undesirable side effects. This study aimed to explore the potential usage of Cassiae semen (CS), a well-known traditional Chinese medicine used to treat obesity. A computational molecular docking study was performed to determine the binding mechanism of CS compounds to the 5-HT2C receptors in both active, agonist-bound and inactive, antagonist-bound conformations. By comparing binding poses and predicted relative binding affinities towards the active or inactive forms of the receptor, we hypothesise that two of the CS compounds studied may be potent agonists which may mimic the appetite suppression effects of lorcaserin: obtusifoliol and cassiaside B2. Furthermore, two ligands, beta-sitosterol and juglanin, were predicted to bind favourably to 5-HT2C outside of the known agonist binding pocket in the active receptor, suggesting that such ligands may serve as positive allosteric modulators of 5-HT2C receptor function. Overall, this study proposed several CS compounds which may be responsible for exerting anti-obesity effects via appetite suppression by 5-HT2C receptor activation. Full article

(This article belongs to the Special Issue Protein–Ligand Interactions: Deciphering the Molecular Targets and the Mechanisms of Action of Drugs and Natural Compounds)

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28 pages, 3701 KiB

Open AccessArticle

Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study

by Antonella Di Sotto, Hamid Irannejad, Margherita Eufemi, Romina Mancinelli, Lorena Abete, Caterina Loredana Mammola, Fabio Altieri, Gabriela Mazzanti and Silvia Di Giacomo

Int. J. Mol. Sci. 2020, 21(2), 633; https://doi.org/10.3390/ijms21020633 - 17 Jan 2020

Cited by 23 | Viewed by 4290

Abstract

Doxorubicin represents a valuable choice for different cancers, although the severe side effects occurring at the high effective dose limits its clinical use. In the present study, potential strategies to potentiate low-dose doxorubicin efficacy, including a metronomic schedule, characterized by a short and repeated exposure to the anticancer drug, and the combination with the natural chemosensitizing sesquiterpenes β-caryophyllene and β-caryophyllene oxide, were assessed in human hepatoma HepG2 cells. The involvement of P-glycoprotein (P-gp) in the HepG2–chemosensitization to doxorubicin was evaluated. Also, the direct interaction of caryophyllene sesquiterpenes with P-gp was characterized by molecular docking and dynamic simulation studies. A metronomic schedule allowed us to enhance the low-dose doxorubicin cytotoxicity and the combination with caryophyllane sesquiterpenes further potentiated this effect. Also, an increased intracellular accumulation of doxorubicin and rhodamine 123 induced by caryophyllane sesquiterpenes was found, thus suggesting their interference with P-gp function. A lowered expression of P-gp induced by the combinations, with respect to doxorubicin alone, was observed too. Docking studies found that the binding site of caryophyllane sesquiterpene was next to the ATP binding domain of P-gp and that β-caryophyllene possessed the stronger binding affinity and higher inhibition potential calculated by MM-PBSA. Present findings strengthen our hypothesis about the potential chemosensitizing power of caryophyllane sesquiterpenes and suggest that combining a chemosensitizer and a metronomic schedule can represent a suitable strategy to overcome drawbacks of doxorubicin chemotherapy while exploiting its powerful activity. Full article

(This article belongs to the Special Issue Protein–Ligand Interactions: Deciphering the Molecular Targets and the Mechanisms of Action of Drugs and Natural Compounds)

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16 pages, 2693 KiB

Open AccessArticle

Uncovering the Pharmacological Mechanism of Stemazole in the Treatment of Neurodegenerative Diseases Based on a Network Pharmacology Approach

by Jing Zhang, Huajun Li, Yubo Zhang, Chaoran Zhao, Yizi Zhu and Mei Han

Int. J. Mol. Sci. 2020, 21(2), 427; https://doi.org/10.3390/ijms21020427 - 9 Jan 2020

Cited by 17 | Viewed by 4578

Abstract

Stemazole exerts potent pharmacological effects against neurodegenerative diseases and protective effects in stem cells. However, on the basis of the current understanding, the molecular mechanisms underlying the effects of stemazole in the treatment of Alzheimer’s disease and Parkinson’s disease have not been fully elucidated. In this study, a network pharmacology-based strategy integrating target prediction, network construction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking was adopted to predict the targets of stemazole relevant to the treatment of neurodegenerative diseases and to further explore the involved pharmacological mechanisms. The majority of the predicted targets were highly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. RAC-alpha serine/threonine-protein kinase (AKT1), caspase-3 (CASP3), caspase-8 (CASP8), mitogen-activated protein kinase 8 (MAPK8), and mitogen-activated protein kinase 14 (MAPK14) are the core targets regulated by stemazole and play a central role in its anti-apoptosis effects. This work provides a scientific basis for further elucidating the mechanism underlying the effects of stemazole in the treatment of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Protein–Ligand Interactions: Deciphering the Molecular Targets and the Mechanisms of Action of Drugs and Natural Compounds)

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28 pages, 7370 KiB

Open AccessArticle

Model Optimization and In Silico Analysis of Potential Dipeptidyl Peptidase IV Antagonists from GC-MS Identified Compounds in Nauclea latifolia Leaf Extracts

by Franklyn Nonso Iheagwam, Olubanke Olujoke Ogunlana and Shalom Nwodo Chinedu

Int. J. Mol. Sci. 2019, 20(23), 5913; https://doi.org/10.3390/ijms20235913 - 25 Nov 2019

Cited by 13 | Viewed by 3476

Abstract

Dipeptidyl peptidase IV (DPP-IV) is a pharmacotherapeutic target in type 2 diabetes. Inhibitors of this enzyme constitute a new class of drugs used in the treatment and management of type 2 diabetes. In this study, phytocompounds in Nauclea latifolia (NL) leaf extracts, identified using gas chromatography–mass spectroscopy (GC-MS), were tested for potential antagonists of DPP-IV via in silico techniques. Phytocompounds present in N. latifolia aqueous (NLA) and ethanol (NLE) leaf extracts were identified using GC–MS. DPP-IV model optimization and molecular docking of the identified compounds/standard inhibitors in the binding pocket was simulated. Drug-likeness, pharmacokinetic and pharmacodynamic properties of promising docked leads were also predicted. Results showed the presence of 50 phytocompounds in NL extracts of which only 2-O-p-methylphenyl-1-thio-β-d-glucoside, 3-tosylsedoheptulose, 4-benzyloxy-6-hydroxymethyl-tetrahydropyran-2,3,5-triol and vitamin E exhibited comparable or better binding iGEMDOCK and AutoDock Vina scores than the clinically prescribed standards. These four compounds exhibited promising drug-likeness as well as absorption, distribution, metabolism, excretion and toxicity (ADMET) properties suggesting their candidature as novel leads for developing DPP-IV inhibitors. Full article

(This article belongs to the Special Issue Protein–Ligand Interactions: Deciphering the Molecular Targets and the Mechanisms of Action of Drugs and Natural Compounds)

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15 pages, 2880 KiB

Open AccessArticle

Systematic Elucidation of the Mechanism of Genistein against Pulmonary Hypertension via Network Pharmacology Approach

by Yucai Chen, Di Chen, Sijia Liu, Tianyi Yuan, Jian Guo, Lianhua Fang and Guanhua Du

Int. J. Mol. Sci. 2019, 20(22), 5569; https://doi.org/10.3390/ijms20225569 - 7 Nov 2019

Cited by 24 | Viewed by 4366

Abstract

: Numerous studies have shown that genistein has a good therapeutic effect on pulmonary hypertension (PH). However, there has been no systematic research performed yet to elucidate its exact mechanism of action in relation to PH. In this study, a systemic pharmacology approach was employed to analyze the anti-PH effect of genistein. Firstly, the preliminary predicted targets of genistein against PH were obtained through database mining, and then the correlation of these targets with PH was analyzed. After that, the protein-protein interaction network was constructed, and the functional annotation and cluster analysis were performed to obtain the core targets and key pathways involved in exerting the anti-PH effect of genistein. Finally, the mechanism was further analyzed via molecular docking of genistein with peroxisome proliferator-activated receptor γ (PPARγ). The results showed that the anti-PH effect of genistein may be closely related to PPARγ, apoptotic signaling pathway, and the nitric oxide synthesis process. This study not only provides new insights into the mechanism of genistein against PH, but also provides novel ideas for network approaches for PH-related research. Full article

(This article belongs to the Special Issue Protein–Ligand Interactions: Deciphering the Molecular Targets and the Mechanisms of Action of Drugs and Natural Compounds)

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12 pages, 3065 KiB

Open AccessArticle

Anti-Inflammatory and Anti-Apoptotic Effects of Stybenpropol A on Human Umbilical Vein Endothelial Cells

by Li Zhang, Feifei Wang, Qing Zhang, Qiuming Liang, Shumei Wang, Minghua Xian and Feng Wang

Int. J. Mol. Sci. 2019, 20(21), 5383; https://doi.org/10.3390/ijms20215383 - 29 Oct 2019

Cited by 14 | Viewed by 2848

Abstract

Inflammation is a key mediator in the progression of atherosclerosis (AS). Benzoinum, a resin secreted from the bark of Styrax tonkinensis, has been widely used as a form of traditional Chinese medicine in clinical settings to enhance cardiovascular function, but the active components of the resin responsible for those pharmaceutical effects remain unclear. To better clarify these components, a new phenylpropane derivative termed stybenpropol A was isolated from benzoinum and characterized via comprehensive spectra a nalysis. We further assessed how this phenylpropane derivative affected treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α). Our results revealed that stybenpropol A reduced soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-8 (IL-8), and interleukin-1β (IL-1β) expression by ELISA, inhibited apoptosis, and accelerated nitric oxide (NO) release in TNF-α-treated HUVECs. We further found that stybenpropol A decreased VCAM-1, ICAM-1, Bax, and caspase-9 protein levels, and increased the protein levels of Bcl-2, IKK-β, and IκB-α. This study identified a new, natural phenylpropane derivative of benzoinum, and is the first to reveal its cytoprotective effects in the context of TNF-α-treated HUVECs via regulation of the NF-κB and caspase-9 signaling pathways. Full article

(This article belongs to the Special Issue Protein–Ligand Interactions: Deciphering the Molecular Targets and the Mechanisms of Action of Drugs and Natural Compounds)

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16 pages, 3709 KiB

Open AccessArticle

Deoxypodophyllotoxin Exerts Anti-Cancer Effects on Colorectal Cancer Cells Through Induction of Apoptosis and Suppression of Tumorigenesis

by Chathurika D. B. Gamage, So-Yeon Park, Yi Yang, Rui Zhou, İsa Taş, Woo Kyun Bae, Kyung Keun Kim, Jung-Hyun Shim, Eunae Kim, Goo Yoon and Hangun Kim

Int. J. Mol. Sci. 2019, 20(11), 2612; https://doi.org/10.3390/ijms20112612 - 28 May 2019

Cited by 24 | Viewed by 3878

Abstract

Deoxypodophyllotoxin (DPT) is a cyclolignan compound that exerts anti-cancer effects against various types of cancers. DPT induces apoptosis and inhibits the growth of breast, brain, prostate, gastric, lung, and cervical tumors. In this study, we sought to determine the effect of DPT on cell proliferation, apoptosis, motility, and tumorigenesis of three colorectal cancer (CRC) cell lines: HT29, DLD1, and Caco2. DPT inhibited the proliferation of these cells. Specifically, the compound-induced mitotic arrest in CRC cells by destabilizing microtubules and activating the mitochondrial apoptotic pathway via regulation of B-cell lymphoma 2 (Bcl-2) family proteins (increasing Bcl-2 associated X (BAX) and decreasing B-cell lymphoma-extra-large (Bcl-xL)) ultimately led to caspase-mediated apoptosis. In addition, DPT inhibited tumorigenesis in vitro, and in vivo skin xenograft experiments revealed that DPT significantly decreased tumor size and tumor weight. Taken together, our results suggest DPT to be a potent compound that is suitable for further exploration as a novel chemotherapeutic for human CRC. Full article

(This article belongs to the Special Issue Protein–Ligand Interactions: Deciphering the Molecular Targets and the Mechanisms of Action of Drugs and Natural Compounds)

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Review

Jump to: Research

18 pages, 5014 KiB

Open AccessReview

The Retinoid and Non-Retinoid Ligands of the Rod Visual G Protein-Coupled Receptor

by Joseph T. Ortega and Beata Jastrzebska

Int. J. Mol. Sci. 2019, 20(24), 6218; https://doi.org/10.3390/ijms20246218 - 10 Dec 2019

Cited by 14 | Viewed by 5557

Abstract

G protein-coupled receptors (GPCRs) play a predominant role in the drug discovery effort. These cell surface receptors are activated by a variety of specific ligands that bind to the orthosteric binding pocket located in the extracellular part of the receptor. In addition, the potential binding sites located on the surface of the receptor enable their allosteric modulation with critical consequences for their function and pharmacology. For decades, drug discovery focused on targeting the GPCR orthosteric binding sites. However, finding that GPCRs can be modulated allosterically opened a new venue for developing novel pharmacological modulators with higher specificity. Alternatively, focus on discovering of non-retinoid small molecules beneficial in retinopathies associated with mutations in rhodopsin is currently a fast-growing pharmacological field. In this review, we summarize the accumulated knowledge on retinoid ligands and non-retinoid modulators of the light-sensing GPCR, rhodopsin and their potential in combating the specific vision-related pathologies. Also, recent findings reporting the potential of biologically active compounds derived from natural products as potent rod opsin modulators with beneficial effects against degenerative diseases related to this receptor are highlighted here. Full article

(This article belongs to the Special Issue Protein–Ligand Interactions: Deciphering the Molecular Targets and the Mechanisms of Action of Drugs and Natural Compounds)

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