3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors
Spleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, and cancers. Significant attempts have been undertaken in recent years to develop SYK inhi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-06-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2022.909111/full |
| _version_ | 1818549324464783360 |
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| author | Vikas Kumar Shraddha Parate Danishuddin Amir Zeb Pooja Singh Gihwan Lee Tae Sung Jung Keun Woo Lee Min Woo Ha Min Woo Ha |
| author_facet | Vikas Kumar Shraddha Parate Danishuddin Amir Zeb Pooja Singh Gihwan Lee Tae Sung Jung Keun Woo Lee Min Woo Ha Min Woo Ha |
| author_sort | Vikas Kumar |
| collection | DOAJ |
| description | Spleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, and cancers. Significant attempts have been undertaken in recent years to develop SYK inhibitors; however, limited success has been achieved due to poor pharmacokinetics and adverse effects of inhibitors. The primary goal of this research was to identify potential inhibitors having high affinity, selectivity based on key molecular interactions, and good drug-like properties than the available inhibitor, fostamatinib. In this study, a 3D-QSAR model was built for SYK based on known inhibitor IC50 values. The best pharmacophore model was then used as a 3D query to screen a drug-like database to retrieve hits with novel chemical scaffolds. The obtained compounds were subjected to binding affinity prediction using the molecular docking approach, and the results were subsequently validated using molecular dynamics (MD) simulations. The simulated compounds were ranked according to binding free energy (ΔG), and the binding affinity was compared with fostamatinib. The binding mode analysis of selected compounds revealed that the hit compounds form hydrogen bond interactions with hinge region residue Ala451, glycine-rich loop residue Lys375, Ser379, and DFG motif Asp512. Identified hits were also observed to form a desirable interaction with Pro455 and Asn457, the rare feature observed in SYK inhibitors. Therefore, we argue that identified hit compounds ZINC98363745, ZINC98365358, ZINC98364133, and ZINC08789982 may help in drug design against SYK. |
| first_indexed | 2024-12-12T08:31:52Z |
| format | Article |
| id | doaj.art-ea1eb675088e4e62bd07745f8e6cee97 |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-12-12T08:31:52Z |
| publishDate | 2022-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-ea1eb675088e4e62bd07745f8e6cee972022-12-22T00:31:05ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882022-06-011210.3389/fcimb.2022.9091119091113D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase InhibitorsVikas Kumar0Shraddha Parate1 Danishuddin2Amir Zeb3Pooja Singh4Gihwan Lee5Tae Sung Jung6Keun Woo Lee7Min Woo Ha8Min Woo Ha9Department of Bio & Medical Big Data (BK4 Program), Division of Life Sciences, Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), Jinju, South KoreaDivision of Applied Life Science, Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU), Jinju, South KoreaDepartment of Bio & Medical Big Data (BK4 Program), Division of Life Sciences, Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), Jinju, South KoreaThe Interdisciplinary Graduate Program in Integrative Biotechnology and Translational Medicine, Yonsei University, Incheon, South KoreaDivision of Applied Life Science, Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU), Jinju, South KoreaDivision of Applied Life Science, Plant Molecular Biology and Biotechnology Research Center (PMBBRC), Gyeongsang National University (GNU), Jinju, South KoreaLaboratory of Aquatic Animal Diseases, Research Institute of Natural Science, College of Veterinary Medicine, Gyeongsang National University, Jinju-si, South KoreaDepartment of Bio & Medical Big Data (BK4 Program), Division of Life Sciences, Research Institute of Natural Science (RINS), Gyeongsang National University (GNU), Jinju, South KoreaJeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University, Jeju, South KoreaInterdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju, South KoreaSpleen tyrosine kinase (SYK) is an essential mediator of immune cell signaling and has been anticipated as a therapeutic target for autoimmune diseases, notably rheumatoid arthritis, allergic rhinitis, asthma, and cancers. Significant attempts have been undertaken in recent years to develop SYK inhibitors; however, limited success has been achieved due to poor pharmacokinetics and adverse effects of inhibitors. The primary goal of this research was to identify potential inhibitors having high affinity, selectivity based on key molecular interactions, and good drug-like properties than the available inhibitor, fostamatinib. In this study, a 3D-QSAR model was built for SYK based on known inhibitor IC50 values. The best pharmacophore model was then used as a 3D query to screen a drug-like database to retrieve hits with novel chemical scaffolds. The obtained compounds were subjected to binding affinity prediction using the molecular docking approach, and the results were subsequently validated using molecular dynamics (MD) simulations. The simulated compounds were ranked according to binding free energy (ΔG), and the binding affinity was compared with fostamatinib. The binding mode analysis of selected compounds revealed that the hit compounds form hydrogen bond interactions with hinge region residue Ala451, glycine-rich loop residue Lys375, Ser379, and DFG motif Asp512. Identified hits were also observed to form a desirable interaction with Pro455 and Asn457, the rare feature observed in SYK inhibitors. Therefore, we argue that identified hit compounds ZINC98363745, ZINC98365358, ZINC98364133, and ZINC08789982 may help in drug design against SYK.https://www.frontiersin.org/articles/10.3389/fcimb.2022.909111/fullSYK inhibitor3D QSARpharmacophoreautoimmune diseasesmolecular dockingMD simulation |
| spellingShingle | Vikas Kumar Shraddha Parate Danishuddin Amir Zeb Pooja Singh Gihwan Lee Tae Sung Jung Keun Woo Lee Min Woo Ha Min Woo Ha 3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors Frontiers in Cellular and Infection Microbiology SYK inhibitor 3D QSAR pharmacophore autoimmune diseases molecular docking MD simulation |
| title | 3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors |
| title_full | 3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors |
| title_fullStr | 3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors |
| title_full_unstemmed | 3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors |
| title_short | 3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors |
| title_sort | 3d qsar based pharmacophore modeling virtual screening and molecular dynamics simulations for the identification of spleen tyrosine kinase inhibitors |
| topic | SYK inhibitor 3D QSAR pharmacophore autoimmune diseases molecular docking MD simulation |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2022.909111/full |
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