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Marine Drugs
Special Issues
Marine Drug Discovery through Molecular Docking
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Marine Drug Discovery through Molecular Docking

A special issue of Marine Drugs (ISSN 1660-3397). This special issue belongs to the section "Marine Pharmacology".

Deadline for manuscript submissions: closed (30 September 2024) | Viewed by 15142

Special Issue Editors

Prof. Dr. Ines Mancini

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Guest Editor
Bioorganic Chemistry Laboratory, Department of Physics, University of Trento, Via Sommarive 14, I-38123 Povo-Trento, Italy
Interests: marine natural products; structural characterization; medicinal chemistry; structure–activity relationship (SAR) studies; organic synthesis; virtual screening
Special Issues, Collections and Topics in MDPI journals
Dr. Andrea Defant

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Guest Editor
External Collaborator of Bioorganic Chemistry Laboratory, Department of Physics, University of Trento, Via Sommarive 14, I-38123 Povo-Trento, Italy
Interests: molecular docking; molecular dynamics; density functional theory (DFT) calculation; in silico screening; drug design; organic synthesis.

Special Issue Information

Dear Colleagues,                

Marine natural products have increasingly become major players in recent drug discovery. Due to their peculiar structures, they are able to enrich the chemical space of biologically active molecules. The study of them in medicinal chemistry is carried out using an iterative transdisciplinary approach, employing innovative technologies which benefit from spectroscopic, synthetic and computational tools. In the rational design of a potential drug inspired by a natural hit scaffold, the optimization takes advantage of in silico screening where docking with macromolecular targets is able to select the best candidates, later synthesised for biological investigation. Through structure–activity relationship (SAR) studies, the most promising candidates are identified, showing the best physico-chemical and pharmacological properties, which are predicted using a computational approach.

The purpose of this Special Issue is to collect papers on these topics. We strongly encourage the submission of articles showcasing your current research as well as critical overviews of the existing literature.

Prof. Ines Mancini
Dr. Andrea Defant
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. Marine Drugs 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

  • molecular docking
  • marine metabolites
  • medicinal chemistry
  • in silico screening
  • drug-target interaction
  • drug design
  • structure-activity relationship (SAR)
  • lead optimization

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Published Papers (7 papers)

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Research

16 pages, 3715 KiB  
Article
Screening for Potential Antiviral Compounds from Cyanobacterial Secondary Metabolites Using Machine Learning
by Tingrui Zhang, Geyao Sun, Xueyu Cheng, Cheng Cao, Zhonghua Cai and Jin Zhou
Mar. Drugs 2024, 22(11), 501; https://doi.org/10.3390/md22110501 - 5 Nov 2024
Viewed by 1289
Abstract
The secondary metabolites of seawater and freshwater blue-green algae are a rich natural product pool containing diverse compounds with various functions, including antiviral compounds; however, high-efficiency methods to screen such compounds are lacking. Advanced virtual screening techniques can significantly reduce the time and [...] Read more.
The secondary metabolites of seawater and freshwater blue-green algae are a rich natural product pool containing diverse compounds with various functions, including antiviral compounds; however, high-efficiency methods to screen such compounds are lacking. Advanced virtual screening techniques can significantly reduce the time and cost of novel antiviral drug identification. In this study, we used a cyanobacterial secondary metabolite library as an example and trained three models to identify compounds with potential antiviral activity using a machine learning method based on message-passing neural networks. Using this method, 364 potential antiviral compounds were screened from >2000 cyanobacterial secondary metabolites, with amides predominating (area under the receiver operating characteristic curve value: 0.98). To verify the actual effectiveness of the candidate antiviral compounds, HIV virus reverse transcriptase (HIV-1 RT) was selected as a target to evaluate their antiviral potential. Molecular docking experiments demonstrated that candidate compounds, including kororamide, mollamide E, nostopeptolide A3, anachelin-H, and kasumigamide, produced relatively robust non-covalent bonding interactions with the RNase H active site on HIV-1 RT, supporting the effectiveness of the proposed screening model. Our data demonstrate that artificial intelligence-based screening methods are effective tools for mining potential antiviral compounds, which can facilitate the exploration of various natural product libraries. Full article
(This article belongs to the Special Issue Marine Drug Discovery through Molecular Docking)
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17 pages, 4712 KiB  
Article
Mutagenesis of the Peptide Inhibitor of ASIC3 Channel Introduces Binding to Thumb Domain of ASIC1a but Reduces Analgesic Activity
by Timur A. Khasanov, Ekaterina E. Maleeva, Sergey G. Koshelev, Victor A. Palikov, Yulia A. Palikova, Igor A. Dyachenko, Sergey A. Kozlov, Yaroslav A. Andreev and Dmitry I. Osmakov
Mar. Drugs 2024, 22(9), 382; https://doi.org/10.3390/md22090382 - 24 Aug 2024
Viewed by 1373
Abstract
Acid-sensing ion channels (ASICs), which act as proton-gating sodium channels, have garnered attention as pharmacological targets. ASIC1a isoform, notably prevalent in the central nervous system, plays an important role in synaptic plasticity, anxiety, neurodegeneration, etc. In the peripheral nervous system, ASIC1a shares prominence [...] Read more.
Acid-sensing ion channels (ASICs), which act as proton-gating sodium channels, have garnered attention as pharmacological targets. ASIC1a isoform, notably prevalent in the central nervous system, plays an important role in synaptic plasticity, anxiety, neurodegeneration, etc. In the peripheral nervous system, ASIC1a shares prominence with ASIC3, the latter well established for its involvement in pain signaling, mechanical sensitivity, and inflammatory hyperalgesia. However, the precise contributions of ASIC1a in peripheral functions necessitate thorough investigation. To dissect the specific roles of ASICs, peptide ligands capable of modulating these channels serve as indispensable tools. Employing molecular modeling, we designed the peptide targeting ASIC1a channel from the sea anemone peptide Ugr9-1, originally targeting ASIC3. This peptide (A23K) retained an inhibitory effect on ASIC3 (IC50 9.39 µM) and exhibited an additional inhibitory effect on ASIC1a (IC50 6.72 µM) in electrophysiological experiments. A crucial interaction between the Lys23 residue of the A23K peptide and the Asp355 residue in the thumb domain of the ASIC1a channel predicted by molecular modeling was confirmed by site-directed mutagenesis of the channel. However, A23K peptide revealed a significant decrease in or loss of analgesic properties when compared to the wild-type Ugr9-1. In summary, using A23K, we show that negative modulation of the ASIC1a channel in the peripheral nervous system can compromise the efficacy of an analgesic drug. These results provide a compelling illustration of the complex balance required when developing peripheral pain treatments targeting ASICs. Full article
(This article belongs to the Special Issue Marine Drug Discovery through Molecular Docking)
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14 pages, 3178 KiB  
Article
Inhibition of Soluble Epoxide Hydrolase by Cembranoid Diterpenes from Soft Coral Sinularia maxima: Enzyme Kinetics, Molecular Docking, and Molecular Dynamics
by Nguyen Viet Phong, Nguyen Phuong Thao, Le Ba Vinh, Bui Thi Thuy Luyen, Chau Van Minh and Seo Young Yang
Mar. Drugs 2024, 22(8), 373; https://doi.org/10.3390/md22080373 - 17 Aug 2024
Cited by 1 | Viewed by 1375
Abstract
Soluble epoxide hydrolase (sEH) is essential for converting epoxy fatty acids, such as epoxyeicosatrienoic acids (EETs), into their dihydroxy forms. EETs play a crucial role in regulating blood pressure, mediating anti-inflammatory responses, and modulating pain, making sEH a key target for therapeutic interventions. [...] Read more.
Soluble epoxide hydrolase (sEH) is essential for converting epoxy fatty acids, such as epoxyeicosatrienoic acids (EETs), into their dihydroxy forms. EETs play a crucial role in regulating blood pressure, mediating anti-inflammatory responses, and modulating pain, making sEH a key target for therapeutic interventions. Current research is increasingly focused on identifying sEH inhibitors from natural sources, particularly marine environments, which are rich in bioactive compounds due to their unique metabolic adaptations. In this study, the sEH inhibitory activities of ten cembranoid diterpenes (1–10) isolated from the soft coral Sinularia maxima were evaluated. Among them, compounds 3 and 9 exhibited considerable sEH inhibition, with IC50 values of 70.68 μM and 78.83 μM, respectively. Enzyme kinetics analysis revealed that these two active compounds inhibit sEH through a non-competitive mode. Additionally, in silico approaches, including molecular docking and molecular dynamics simulations, confirmed their stability and interactions with sEH, highlighting their potential as natural therapeutic agents for managing cardiovascular and inflammatory diseases. Full article
(This article belongs to the Special Issue Marine Drug Discovery through Molecular Docking)
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19 pages, 4616 KiB  
Article
Green Seaweed Caulerpa racemosa as a Novel Non-Small Cell Lung Cancer Inhibitor in Overcoming Tyrosine Kinase Inhibitor Resistance: An Analysis Employing Network Pharmacology, Molecular Docking, and In Vitro Research
by Vincent Lau, Fahrul Nurkolis, Moon Nyeo Park, Didik Setyo Heriyanto, Nurpudji Astuti Taslim, Trina Ekawati Tallei, Happy Kurnia Permatasari, Raymond R. Tjandrawinata, Seungjoon Moon and Bonglee Kim
Mar. Drugs 2024, 22(6), 272; https://doi.org/10.3390/md22060272 - 12 Jun 2024
Cited by 2 | Viewed by 3134
Abstract
The marine environment provides a rich source of distinct creatures containing potentially revolutionary bioactive chemicals. One of these organisms is Caulerpa racemosa, a type of green algae known as green seaweed, seagrapes, or green caviar. This organism stands out because it has [...] Read more.
The marine environment provides a rich source of distinct creatures containing potentially revolutionary bioactive chemicals. One of these organisms is Caulerpa racemosa, a type of green algae known as green seaweed, seagrapes, or green caviar. This organism stands out because it has great promise for use in medicine, especially in the study of cancer. Through the utilization of computational modeling (in silico) and cellular laboratory experiments (in vitro), the chemical components included in the green seaweed C. racemosa were effectively analyzed, uncovering its capability to treat non-small cell lung cancer (NSCLC). The study specifically emphasized blocking SRC, STAT3, PIK3CA, MAPK1, EGFR, and JAK1 using molecular docking and in vitro. These proteins play a crucial role in the EGFR Tyrosine Kinase Inhibitor Resistance pathway in NSCLC. The chemical Caulersin (C2) included in C. racemosa extract (CRE) has been identified as a potent and effective agent in fighting against non-small cell lung cancer (NSCLC), both in silico and in vitro. CRE and C2 showed a level of inhibition similar to that of osimertinib (positive control/NSCLC drug). Full article
(This article belongs to the Special Issue Marine Drug Discovery through Molecular Docking)
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15 pages, 1736 KiB  
Article
Structural Insights into the Marine Alkaloid Discorhabdin G as a Scaffold towards New Acetylcholinesterase Inhibitors
by Andrea Defant, Giacomo Carloni, Nicole Innocenti, Tomaž Trobec, Robert Frangež, Kristina Sepčić and Ines Mancini
Mar. Drugs 2024, 22(4), 173; https://doi.org/10.3390/md22040173 - 12 Apr 2024
Viewed by 2135
Abstract
In this study, Antarctic Latrunculia sponge-derived discorhabdin G was considered a hit for developing potential lead compounds acting as cholinesterase inhibitors. The hypothesis on the pharmacophore moiety suggested through molecular docking allowed us to simplify the structure of the metabolite. ADME prediction and [...] Read more.
In this study, Antarctic Latrunculia sponge-derived discorhabdin G was considered a hit for developing potential lead compounds acting as cholinesterase inhibitors. The hypothesis on the pharmacophore moiety suggested through molecular docking allowed us to simplify the structure of the metabolite. ADME prediction and drug-likeness consideration provided valuable support in selecting 5-methyl-2H-benzo[h]imidazo[1,5,4-de]quinoxalin-7(3H)-one as a candidate molecule. It was synthesized in a four-step sequence starting from 2,3-dichloronaphthalene-1,4-dione and evaluated as an inhibitor of electric eel acetylcholinesterase (eeAChE), human recombinant AChE (hAChE), and horse serum butyrylcholinesterase (BChE), together with other analogs obtained by the same synthesis. The candidate molecule showed a slightly lower inhibitory potential against eeAChE but better inhibitory activity against hAChE than discorhabdin G, with a higher selectivity for AChEs than for BChE. It acted as a reversible competitive inhibitor, as previously observed for the natural alkaloid. The findings from the in vitro assay were relatively consistent with the data available from the AutoDock Vina and Protein-Ligand ANTSystem (PLANTS) calculations. Full article
(This article belongs to the Special Issue Marine Drug Discovery through Molecular Docking)
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19 pages, 9574 KiB  
Article
Identification of PLK1-PBD Inhibitors from the Library of Marine Natural Products: 3D QSAR Pharmacophore, ADMET, Scaffold Hopping, Molecular Docking, and Molecular Dynamics Study
by Nan Zhou, Chuangze Zheng, Huiting Tan and Lianxiang Luo
Mar. Drugs 2024, 22(2), 83; https://doi.org/10.3390/md22020083 - 10 Feb 2024
Cited by 6 | Viewed by 2526
Abstract
PLK1 is found to be highly expressed in various types of cancers, but the development of inhibitors for it has been slow. Most inhibitors are still in clinical stages, and many lack the necessary selectivity and anti-tumor effects. This study aimed to create [...] Read more.
PLK1 is found to be highly expressed in various types of cancers, but the development of inhibitors for it has been slow. Most inhibitors are still in clinical stages, and many lack the necessary selectivity and anti-tumor effects. This study aimed to create new inhibitors for the PLK1-PBD by focusing on the PBD binding domain, which has the potential for greater selectivity. A 3D QSAR model was developed using a dataset of 112 compounds to evaluate 500 molecules. ADMET prediction was then used to select three molecules with strong drug-like characteristics. Scaffold hopping was employed to reconstruct 98 new compounds with improved drug-like properties and increased activity. Molecular docking was used to compare the efficient compound abbapolin, confirming the high-activity status of [(14S)-14-hydroxy-14-(pyridin-2-yl)tetradecyl]ammonium,[(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium. Molecular dynamics simulations and MMPBSA were conducted to evaluate the stability of the compounds in the presence of proteins. An in-depth analysis of [(14S)-15-(2-furyl)-14-hydroxypentadecyl]ammonium and [(14S)-14-hydroxy-14-phenyltetradecyl]ammonium identified them as potential candidates for PLK1 inhibitors. Full article
(This article belongs to the Special Issue Marine Drug Discovery through Molecular Docking)
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21 pages, 7947 KiB  
Article
In Silico Analysis of USP7 Inhibitors Based on Building QSAR Models and Fragment Design for Screening Marine Compound Libraries
by Huiting Tan, Chenying Li, Tianli Lai and Lianxiang Luo
Mar. Drugs 2024, 22(1), 1; https://doi.org/10.3390/md22010001 - 19 Dec 2023
Cited by 3 | Viewed by 2310
Abstract
USP7 is highly expressed in a variety of tumors and is thought to play a major role in cancer development. However, there are no drugs available to target USP7, so there is a need to develop new USP7 inhibitors. In this study, AutoQSAR, [...] Read more.
USP7 is highly expressed in a variety of tumors and is thought to play a major role in cancer development. However, there are no drugs available to target USP7, so there is a need to develop new USP7 inhibitors. In this study, AutoQSAR, multiple linear regression, and Naive Bayesian models were constructed using 543 compounds and used to analyze marine compounds. After selecting 240 small molecules for molecular docking with Maestro, MOE, and GOLD, better small molecules than the positive compound P217564 were screened. The molecular structure of “1, 2-dibromobenzene” was optimized to improve the binding effect of the protein, and 10 optimized compounds in ADMET performed well during the screening process. To study the dynamic combination of protein–ligand effect consistency with static molecular docking, 100ns molecular dynamics simulations of candidate compound 1008-1, reference compound P217564, and negative-positive GNE2917 were conducted. The results of molecular docking and molecular dynamics simulation analysis showed that compound 1008-1 maintained a stable conformation with the target protein. Thus, the comprehensive analysis suggests that compound 1008-1 could provide new possibilities for USP7 covalent inhibitor candidates. Full article
(This article belongs to the Special Issue Marine Drug Discovery through Molecular Docking)
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