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Molecular Dynamics Simulation and Computer-Aided Screening of 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 Informatics".

Deadline for manuscript submissions: closed (31 July 2024) | Viewed by 14955

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Special Issue Editors

Prof. Dr. Weiwei Han

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Guest Editor

Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun 130012, China
Interests: the relationship between enzyme structure and function; computer-aided drug design; computational structural biology; machine learning
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Xuemei Pu

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Guest Editor

College of Chemistry, Sichuan University, Chengdu 610064, China
Interests: functional mechanism of disease-related genes and target proteins; computer aided drug design

Special Issue Information

Dear Colleagues,

This Special Issue aims to showcase the applications of natural compounds in virtual molecular dynamics simulation and computer-aided screening. Natural compounds are a type of organic compound widely found in nature, possessing broad biological activities and medicinal values. This Special Issue covers research on virtual molecular dynamics simulation, computer-aided screening, and structure optimization of natural compounds, as well as their applications in drug development and therapy. We welcome original research articles, review articles, and short communications from this field, as well as other articles relevant to this Special Issue.

Topics include, but are not limited to:

Molecular dynamics simulation and of natural compounds;
Computer-aided screening of natural compounds with potential medicinal effects;
Pharmacology and biological activities of natural compounds;
Chemical synthesis and structure optimization of natural compounds;
Drug development and clinical applications of natural compounds.

We hope that this Special Issue will provide a platform for scientists and researchers in the field of natural compounds to promote the exchange of knowledge and academic collaboration

Prof. Dr. Weiwei Han
Prof. Dr. Xuemei Pu
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

molecular dynamics simulation
virtual screening
molecular docking, natural compounds
pharmacology

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Published Papers (7 papers)

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Research

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20 pages, 7443 KiB

Open AccessArticle

Interactions between Inhibitors and 5-Lipoxygenase: Insights from Gaussian Accelerated Molecular Dynamics and Markov State Models

by Yuyang Liu, Kaiyu Wang, Fuyan Cao, Nan Gao and Wannan Li

Int. J. Mol. Sci. 2024, 25(15), 8295; https://doi.org/10.3390/ijms25158295 - 30 Jul 2024

Cited by 2 | Viewed by 1592

Abstract

Inflammation is a protective stress response triggered by external stimuli, with 5-lipoxygenase (5LOX) playing a pivotal role as a potent mediator of the leukotriene (Lts) inflammatory pathway. Nordihydroguaiaretic acid (NDGA) functions as a natural orthosteric inhibitor of 5LOX, while 3-acetyl-11-keto-β-boswellic acid (AKBA) acts as a natural allosteric inhibitor targeting 5LOX. However, the precise mechanisms of inhibition have remained unclear. In this study, Gaussian accelerated molecular dynamics (GaMD) simulation was employed to elucidate the inhibitory mechanisms of NDGA and AKBA on 5LOX. It was found that the orthosteric inhibitor NDGA was tightly bound in the protein’s active pocket, occupying the active site and inhibiting the catalytic activity of the 5LOX enzyme through competitive inhibition. The binding of the allosteric inhibitor AKBA induced significant changes at the distal active site, leading to a conformational shift of residues 168–173 from a loop to an α-helix and significant negative correlated motions between residues 285–290 and 375–400, reducing the distance between these segments. In the simulation, the volume of the active cavity in the stable conformation of the protein was reduced, hindering the substrate’s entry into the active cavity and, thereby, inhibiting protein activity through allosteric effects. Ultimately, Markov state models (MSM) were used to identify and classify the metastable states of proteins, revealing the transition times between different conformational states. In summary, this study provides theoretical insights into the inhibition mechanisms of 5LOX by AKBA and NDGA, offering new perspectives for the development of novel inhibitors specifically targeting 5LOX, with potential implications for anti-inflammatory drug development. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulation and Computer-Aided Screening of Natural Compounds)

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20 pages, 5554 KiB

Open AccessArticle

Identification and Validation of New DNA-PKcs Inhibitors through High-Throughput Virtual Screening and Experimental Verification

by Liujiang Dai, Pengfei Yu, Hongjie Fan, Wei Xia, Yaopeng Zhao, Pengfei Zhang, John Z. H. Zhang, Haiping Zhang and Yang Chen

Int. J. Mol. Sci. 2024, 25(14), 7982; https://doi.org/10.3390/ijms25147982 - 22 Jul 2024

Cited by 2 | Viewed by 1925

Abstract

DNA-PKcs is a crucial protein target involved in DNA repair and response pathways, with its abnormal activity closely associated with the occurrence and progression of various cancers. In this study, we employed a deep learning-based screening and molecular dynamics (MD) simulation-based pipeline, identifying eight candidates for DNA-PKcs targets. Subsequent experiments revealed the effective inhibition of DNA-PKcs-mediated cell proliferation by three small molecules (5025-0002, M769-1095, and V008-1080). These molecules exhibited anticancer activity with IC₅₀ (inhibitory concentration at 50%) values of 152.6 μM, 30.71 μM, and 74.84 μM, respectively. Notably, V008-1080 enhanced homology-directed repair (HDR) mediated by CRISPR/Cas9 while inhibiting non-homologous end joining (NHEJ) efficiency. Further investigations into the structure-activity relationships unveiled the binding sites and critical interactions between these small molecules and DNA-PKcs. This is the first application of DeepBindGCN_RG in a real drug screening task, and the successful discovery of a novel DNA-PKcs inhibitor demonstrates its efficiency as a core component in the screening pipeline. Moreover, this study provides important insights for exploring novel anticancer therapeutics and advancing the development of gene editing techniques by targeting DNA-PKcs. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulation and Computer-Aided Screening of Natural Compounds)

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15 pages, 9059 KiB

Open AccessArticle

Unveiling Anti-Diabetic Potential of Baicalin and Baicalein from Baikal Skullcap: LC–MS, In Silico, and In Vitro Studies

by Wencheng Zhao, Huizi Cui, Kaifeng Liu, Xiaotang Yang, Shu Xing and Wannan Li

Int. J. Mol. Sci. 2024, 25(7), 3654; https://doi.org/10.3390/ijms25073654 - 25 Mar 2024

Cited by 5 | Viewed by 2353

Abstract

Type 2 diabetes mellitus (T2DM) is marked by persistent hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction, imposing substantial health burdens and elevating the risk of systemic complications and cardiovascular diseases. While the pathogenesis of diabetes remains elusive, a cyclical relationship between insulin resistance and inflammation is acknowledged, wherein inflammation exacerbates insulin resistance, perpetuating a deleterious cycle. Consequently, anti-inflammatory interventions offer a therapeutic avenue for T2DM management. In this study, a herb called Baikal skullcap, renowned for its repertoire of bioactive compounds with anti-inflammatory potential, is posited as a promising source for novel T2DM therapeutic strategies. Our study probed the anti-diabetic properties of compounds from Baikal skullcap via network pharmacology, molecular docking, and cellular assays, concentrating on their dual modulatory effects on diabetes through Protein Tyrosine Phosphatase 1B (PTP1B) enzyme inhibition and anti-inflammatory actions. We identified the major compounds in Baikal skullcap using liquid chromatography–mass spectrometry (LC–MS), highlighting six flavonoids, including the well-studied baicalein, as potent inhibitors of PTP1B. Furthermore, cellular experiments revealed that baicalin and baicalein exhibited enhanced anti-inflammatory responses compared to the active constituents of licorice, a known anti-inflammatory agent in TCM. Our findings confirmed that baicalin and baicalein mitigate diabetes via two distinct pathways: PTP1B inhibition and anti-inflammatory effects. Additionally, we have identified six flavonoid molecules with substantial potential for drug development, thereby augmenting the T2DM pharmacotherapeutic arsenal and promoting the integration of herb-derived treatments into modern pharmacology. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulation and Computer-Aided Screening of Natural Compounds)

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16 pages, 8584 KiB

Open AccessArticle

Study on the Mechanism of Interaction between Dipeptidyl Peptidase 4 and Inhibitory Peptides Based on Gaussian Accelerated Molecular Dynamic Simulation

by Yuyang Liu, Wencheng Zhao, Yongxin Jiang, Shu Xing and Wannan Li

Int. J. Mol. Sci. 2024, 25(2), 839; https://doi.org/10.3390/ijms25020839 - 10 Jan 2024

Cited by 3 | Viewed by 1967

Abstract

Dipeptidyl peptidase 4 (DPP4) inhibitors can effectively inhibit the activity of DPP4, increasing the concentrations of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which allows for them to effectively contribute to the reduction of blood sugar levels. Leu-Pro-Ala-Val-Thr-Ile-Arg (LPAVTIR) and Leu-Pro-Pro-Glu-His-Asp-Trp-Arg (LPPEHDWR) were the two peptides with the strongest inhibitory activity against DPP4 selected from silkworm pupa proteins. In this study, four systems were established: Apo (ligand-free DPP4), IPI (IPI-bound DPP4), LPAVTIR (LPAVTIR-bound DPP4), LPPEHDWR (LPPEHDWR-bound DPP4), and Gaussian accelerated molecular dynamic (GaMD) simulation was conducted to investigate the mechanism of action of two inhibitory peptides binding to DPP4. Our study revealed that the LPAVTIR peptide possessed a more stable structure and exhibited a tighter binding to the Ser630 active site in DPP4, thus exhibiting a favorable competitive inhibition effect. In contrast, the LPPEHDWR peptide caused the horizontal α-helix (residues 201–215) composed of Glu205 and Glu206 residues in DPP4 to disappear. The spatial arrangement of active sites Ser630 relative to Glu205 and Glu206 was disrupted, resulting in enzyme inactivation. Moreover, the size of the substrate channel and cavity volume was significantly reduced after the binding of the inhibitory peptide to the protein, which was an important factor in the inhibition of the enzyme activity. A similar effect was also found from IPI (our positive control). By stabilizing the active site of DPP4, the IPI peptide induced the disappearance of the horizontal α-helix and a notable reduction in the active cavity volume. In conclusion, our study provided a solid theoretical foundation for the inhibitory mechanisms of IPI, LPAVTIR, and LPPEHDWR on DPP4, offering valuable insights for advancing the development of drug targets for type 2 diabetes. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulation and Computer-Aided Screening of Natural Compounds)

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16 pages, 5512 KiB

Open AccessArticle

Exploring Major Flavonoid Phytochemicals from Nelumbo nucifera Gaertn. as Potential Skin Anti-Aging Agents: In Silico and In Vitro Evaluations

by Bodee Nutho and Duangjai Tungmunnithum

Int. J. Mol. Sci. 2023, 24(23), 16571; https://doi.org/10.3390/ijms242316571 - 21 Nov 2023

Cited by 9 | Viewed by 2836

Abstract

Nelumbo nucifera Gaertn., an aquatic medicinal plant (Nelumbonaceae family), has a history of use in traditional medicine across various regions. Our previous study demonstrated the skin anti-aging potential of its stamen ethanolic extract by effectively inhibiting collagenase and tyrosinase enzymes. While the major constituents of this extract are well documented, there is a lack of research on the individual compounds’ abilities to inhibit skin aging enzymes. Therefore, this study aimed to evaluate the anti-aging potential of the primary flavonoids found in N. nucifera using both in silico and in vitro approaches. Our initial step involved molecular docking to identify compounds with the potential to inhibit collagenase, elastase, and tyrosinase. Among the seven flavonoids studied, kaempferol-3-O-robinobioside (Kae-3-Rob) emerged as the most promising candidate, exhibiting the highest docking scores for three skin aging-related enzymes. Subsequent enzyme-based inhibition assays confirmed that Kae-3-Rob displayed robust inhibitory activity against collagenase (58.24 ± 8.27%), elastase (26.29 ± 7.16%), and tyrosinase (69.84 ± 6.07%). Furthermore, we conducted extensive 200-ns molecular dynamics (MD) simulations, revealing the stability of the complexes formed between Kae-3-Rob and each enzyme along the MD simulation time. MM/PBSA-based binding free energy calculations indicated the considerably stronger binding affinity of Kae-3-Rob for collagenase and tyrosinase compared to elastase, which was related to the greater percentage of hydrogen bond occupations. These computational findings were consistent with the relatively high inhibitory activity of Kae-3-Rob against collagenase and tyrosinase observed in our in vitro experiment. In conclusion, the results obtained from this comprehensive study suggest that Kae-3-Rob, a key flavonoid from N. nucifera, holds significant potential as a source of bioactive compounds for anti-aging cosmeceutical and other phytopharmaceutical application. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulation and Computer-Aided Screening of Natural Compounds)

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15 pages, 9287 KiB

Open AccessArticle

Functionalized Fullerene Potentially Inhibits SARS-CoV-2 Infection by Modulating Spike Protein Conformational Changes

by Kaifeng Liu, Fangfang Guo, Yingying Ma, Xiangyu Yu, Xueqi Fu, Wannan Li and Weiwei Han

Int. J. Mol. Sci. 2023, 24(19), 14471; https://doi.org/10.3390/ijms241914471 - 23 Sep 2023

Cited by 7 | Viewed by 1705

Abstract

The disease of SARS-CoV-2 has caused considerable morbidity and mortality globally. Spike proteins on the surface of SARS-CoV-2 allow it to bind with human cells, leading to infection. Fullerenes and their derivatives are promising SARS-CoV-2 inhibitors and drug-delivery vehicles. In this study, Gaussian accelerated molecular dynamics simulations and the Markov state model were employed to delve into the inhibitory mechanism of Fullerene–linear-polyglycerol-b-amine sulfate (F–LGPS) on spike proteins. During the study, it was discovered that fullerene derivatives can operate at the interface of the receptor-binding domain (RBD) and the N-terminal domain (NTD), keeping structural domains in a downward conformation. It was also observed that F-LGPS demonstrated superior inhibitory effects on the XBB variant in comparison to the wild-type variant. This study yielded invaluable insights for the potential development of efficient therapeutics targeting the spike protein of SARS-CoV-2. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulation and Computer-Aided Screening of Natural Compounds)

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Review

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15 pages, 3866 KiB

Open AccessReview

Systematic Review of Naturally Derived Substances That Act as Inhibitors of the Nicotine Metabolizing Enzyme Cytochrome P450 2A6

by Haralampos Tzoupis, Konstantinos D. Papavasileiou, Stavros Papatzelos, Angelos Mavrogiorgis, Lefteris C. Zacharia, Georgia Melagraki and Antreas Afantitis

Int. J. Mol. Sci. 2024, 25(15), 8031; https://doi.org/10.3390/ijms25158031 - 23 Jul 2024

Viewed by 1644

Abstract

Tobacco smoking has been highlighted as a major health challenge in modern societies. Despite not causing death directly, smoking has been associated with several health issues, such as cardiovascular diseases, respiratory disorders, and several cancer types. Moreover, exposure to nicotine during pregnancy has been associated with adverse neurological disorders in babies. Nicotine Replacement Therapy (NRT) is the most common strategy employed for smoking cessation, but despite its widespread use, NRT presents with low success and adherence rates. This is attributed partially to the rate of nicotine metabolism by cytochrome P450 2A6 (CYP2A6) in each individual. Nicotine addiction is correlated with the high rate of its metabolism, and thus, novel strategies need to be implemented in NRT protocols. Naturally derived products are a cost-efficient and rich source for potential inhibitors, with the main advantages being their abundance and ease of isolation. This systematic review aims to summarize the natural products that have been identified as CYP2A6 inhibitors, validated through in vitro and/or in vivo assays, and could be implemented as nicotine metabolism inhibitors. The scope is to present the different compounds and highlight their possible implementation in NRT strategies. Additionally, this information would provide valuable insight regarding CYP2A6 inhibitors, that can be utilized in drug development via the use of in silico methodologies and machine-learning models to identify new potential lead compounds for optimization and implementation in NRT regimes. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulation and Computer-Aided Screening of Natural Compounds)

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