A Comprehensive Computational Screening of Phytochemicals Derived from Saudi Medicinal Plants against Human CC Chemokine Receptor 7 to Identify Potential Anti-Cancer Therapeutics
Homeostatic trafficking of immune cells by CC chemokine receptor 7 (CCR7) keeps immune responses and tolerance in a balance. The involvement of this protein in lymph node metastasis in cancer marks CCR7 as a penitential drug target. Using the crystal structure of CCR7, herein, a comprehensive virtua...
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| Format: | Article |
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MDPI AG
2021-10-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/21/6354 |
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| author | Faris Alrumaihi |
| author_facet | Faris Alrumaihi |
| author_sort | Faris Alrumaihi |
| collection | DOAJ |
| description | Homeostatic trafficking of immune cells by CC chemokine receptor 7 (CCR7) keeps immune responses and tolerance in a balance. The involvement of this protein in lymph node metastasis in cancer marks CCR7 as a penitential drug target. Using the crystal structure of CCR7, herein, a comprehensive virtual screening study is presented to filter novel strong CCR7 binding phytochemicals from Saudi medicinal plants that have a higher binding affinity for the intracellular allosteric binding pocket. By doing so, three small natural molecules named as Hit-1 (1,8,10-trihydroxy-3-methoxy-6-methylanthracen-9(4H)-one), Hit-2 (4-(3,4-dimethoxybenzyl)-3-(4-hydroxy-3-methoxybenzyl)dihydrofuran-2(3H)-one), and Hit-3 (10-methyl-12,13-dihydro-[1,2]dioxolo[3,4,5-de]furo[3,2-g]isochromeno[4,3-b]chromen-8-ol) are predicted showing strong binding potential for the CC chemokine receptor 7 allosteric pocket. During molecular dynamics simulations, the compounds were observed in the formation of several chemical bonding of short bond distances. Additionally, the molecules remained in strong contact with the active pocket residues and experienced small conformation changes that seemed to be mediated by the CCR7 loops to properly engage the ligands. Two types of binding energy methods (MM/GBPBSA and WaterSwap) were additionally applied to further validate docking and simulation findings. Both analyses complement the good affinity of compounds for CCR7, the electrostatic and van der Waals energies being the most dominant in intermolecular interactions. The active pocket residue’s role in compounds binding was further evaluated via alanine scanning, which highlighted their importance in natural compounds binding. Additionally, the compounds fulfilled all drug-like rules: Lipinski, Ghose, Veber, Egan, and Muegge passed many safety parameters, making them excellent anti-cancer candidates for experimental testing. |
| first_indexed | 2024-03-10T05:57:01Z |
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| id | doaj.art-9639f069037e41b38bf2ff33e33c3718 |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T05:57:01Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
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| series | Molecules |
| spelling | doaj.art-9639f069037e41b38bf2ff33e33c37182023-11-22T21:20:02ZengMDPI AGMolecules1420-30492021-10-012621635410.3390/molecules26216354A Comprehensive Computational Screening of Phytochemicals Derived from Saudi Medicinal Plants against Human CC Chemokine Receptor 7 to Identify Potential Anti-Cancer TherapeuticsFaris Alrumaihi0Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi ArabiaHomeostatic trafficking of immune cells by CC chemokine receptor 7 (CCR7) keeps immune responses and tolerance in a balance. The involvement of this protein in lymph node metastasis in cancer marks CCR7 as a penitential drug target. Using the crystal structure of CCR7, herein, a comprehensive virtual screening study is presented to filter novel strong CCR7 binding phytochemicals from Saudi medicinal plants that have a higher binding affinity for the intracellular allosteric binding pocket. By doing so, three small natural molecules named as Hit-1 (1,8,10-trihydroxy-3-methoxy-6-methylanthracen-9(4H)-one), Hit-2 (4-(3,4-dimethoxybenzyl)-3-(4-hydroxy-3-methoxybenzyl)dihydrofuran-2(3H)-one), and Hit-3 (10-methyl-12,13-dihydro-[1,2]dioxolo[3,4,5-de]furo[3,2-g]isochromeno[4,3-b]chromen-8-ol) are predicted showing strong binding potential for the CC chemokine receptor 7 allosteric pocket. During molecular dynamics simulations, the compounds were observed in the formation of several chemical bonding of short bond distances. Additionally, the molecules remained in strong contact with the active pocket residues and experienced small conformation changes that seemed to be mediated by the CCR7 loops to properly engage the ligands. Two types of binding energy methods (MM/GBPBSA and WaterSwap) were additionally applied to further validate docking and simulation findings. Both analyses complement the good affinity of compounds for CCR7, the electrostatic and van der Waals energies being the most dominant in intermolecular interactions. The active pocket residue’s role in compounds binding was further evaluated via alanine scanning, which highlighted their importance in natural compounds binding. Additionally, the compounds fulfilled all drug-like rules: Lipinski, Ghose, Veber, Egan, and Muegge passed many safety parameters, making them excellent anti-cancer candidates for experimental testing.https://www.mdpi.com/1420-3049/26/21/6354CC chemokine receptor 7cancerSaudi medicinal plantsnatural productsvirtual screeningMD simulations |
| spellingShingle | Faris Alrumaihi A Comprehensive Computational Screening of Phytochemicals Derived from Saudi Medicinal Plants against Human CC Chemokine Receptor 7 to Identify Potential Anti-Cancer Therapeutics Molecules CC chemokine receptor 7 cancer Saudi medicinal plants natural products virtual screening MD simulations |
| title | A Comprehensive Computational Screening of Phytochemicals Derived from Saudi Medicinal Plants against Human CC Chemokine Receptor 7 to Identify Potential Anti-Cancer Therapeutics |
| title_full | A Comprehensive Computational Screening of Phytochemicals Derived from Saudi Medicinal Plants against Human CC Chemokine Receptor 7 to Identify Potential Anti-Cancer Therapeutics |
| title_fullStr | A Comprehensive Computational Screening of Phytochemicals Derived from Saudi Medicinal Plants against Human CC Chemokine Receptor 7 to Identify Potential Anti-Cancer Therapeutics |
| title_full_unstemmed | A Comprehensive Computational Screening of Phytochemicals Derived from Saudi Medicinal Plants against Human CC Chemokine Receptor 7 to Identify Potential Anti-Cancer Therapeutics |
| title_short | A Comprehensive Computational Screening of Phytochemicals Derived from Saudi Medicinal Plants against Human CC Chemokine Receptor 7 to Identify Potential Anti-Cancer Therapeutics |
| title_sort | comprehensive computational screening of phytochemicals derived from saudi medicinal plants against human cc chemokine receptor 7 to identify potential anti cancer therapeutics |
| topic | CC chemokine receptor 7 cancer Saudi medicinal plants natural products virtual screening MD simulations |
| url | https://www.mdpi.com/1420-3049/26/21/6354 |
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