Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs

Lee, Sang Jae; Choi, Jang‐Sik; Han, Byeong-Gu; Kim, Hyoun Sook; Song, Ho-Juhn; Lee, Jaekyoo; Nam, Seungyoon; Goh, Sung‐Ho; Kim, Jung Ho; Koh, Jai‐Kyoung; Lee, Byung Il

doi:10.1111/febs.13831

Cited by 10 publications

(7 citation statements)

References 44 publications

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“…In addition, SYK has been recently recognized as a prosurvival factor in breast cancers, as well as hematopoietic malignancies (Lee et al, 2016b), representing a strong candidate for anticancer therapy (Geahlen, 2014). In fact, fostamatinib, cerdulatinib, and entospletinib, as Syk inhibitors, are under clinical investigation as single or adjuvant agents, in certain types of leukemia (Coffey et al, 2014; Sharman et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Cancer Transcriptome Dataset Analysis: Comparing Methods of Pathway and Gene Regulatory Network-Based Cluster Identification

Nam

2017

OMICS: A Journal of Integrative Biology

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Cancer transcriptome analysis is one of the leading areas of Big Data science, biomarker, and pharmaceutical discovery, not to forget personalized medicine. Yet, cancer transcriptomics and postgenomic medicine require innovation in bioinformatics as well as comparison of the performance of available algorithms. In this data analytics context, the value of network generation and algorithms has been widely underscored for addressing the salient questions in cancer pathogenesis. Analysis of cancer trancriptome often results in complicated networks where identification of network modularity remains critical, for example, in delineating the “druggable” molecular targets. Network clustering is useful, but depends on the network topology in and of itself. Notably, the performance of different network-generating tools for network cluster (NC) identification has been little investigated to date. Hence, using gastric cancer (GC) transcriptomic datasets, we compared two algorithms for generating pathway versus gene regulatory network-based NCs, showing that the pathway-based approach better agrees with a reference set of cancer-functional contexts. Finally, by applying pathway-based NC identification to GC transcriptome datasets, we describe cancer NCs that associate with candidate therapeutic targets and biomarkers in GC. These observations collectively inform future research on cancer transcriptomics, drug discovery, and rational development of new analysis tools for optimal harnessing of omics data.

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Section: Discussionmentioning

confidence: 99%

Cancer Transcriptome Dataset Analysis: Comparing Methods of Pathway and Gene Regulatory Network-Based Cluster Identification

Nam

2017

OMICS: A Journal of Integrative Biology

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“…Identifying the molecular interaction of the potential inhibitors with the target protein is the key finding of the ligand and structure-based drug discovery reports. Lee et al demonstrated that the SYK ATP-binding site can be divided into four subsites: the hinge region, the glycine-rich loop, the DFG motif, and the activation loop (Figure 3) (Lee et al, 2016). The average structures of complexes calculated from MD simulations were superimposed to study the binding mode.…”

Section: Binding Mode Analysismentioning

confidence: 99%

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors

Kumar

Parate

Danishuddin

et al. 2022

Front. Cell. Infect. Microbiol.

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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.

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“…Molecular docking was carried out for compound 4a, as it showed the most significant anticancer activity against T-47D cancer cell line on, a Core 2 duo 2.20 GHz workstation, 3 GHz memory with windows 7 operating system using molecular operating environment (MOE 2008.10 software) [43]. The crystal structure of the complex of an inhibitorbound tyrosine kinase was downloaded from protein data bank (PDB ID: 4XG7) [44] which has been retrieved from www.rcsb.org [45], and was targeted in the docking experiments. The target was prepared for docking by 3D-protonation and partial charges were computed with subsequent energy minimization and using MOE default parameters under CHARMM27 (an all-atom forcefield parameterized for proteins, DNA and RNA).…”

Section: Molecular Dockingmentioning

confidence: 99%

Design and Synthesis of Novel Pyrazoles, Pyrazolines, and Pyridines From Chalcone Derivatives With the Assessment of Their in Vitro Anticancer Activity Against T-47d and Uacc-257 Cell Lines

2020

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Novel series of pyrazoline carbothioamides, acetyl pyrazoles, pyridine-3-carbonitrile, pyridine-2-carbonitriles, and nicotinonitriles were synthesized. The structures of the newly synthesized compounds were established based on their spectral data, elemental analyses and alternative synthetic routes whenever possible. Also, the newly synthesized compounds were screened for their in vitro anticancer activity against T-47D (breast cancer human cell line) and UACC-257 (melanoma human cell line) by MTT assay (a colorimetric assay for assessing cell metabolic activity). Experimental results demonstrated that compounds 3a, 4a, and 8c showed excellent in vitro activity against against T-47D cell line, while compounds 3d, 6d, and 5b exhibited excellent activity against UACC-257 cell line. Molecular docking studies were performed on compound 4a, as it showed the most promising activity against T-47D cell line, using Molecular Operation Environment (MOE 2008.10) software. Also, drug-likeness, pharmacokinetics, and toxicity assessment studies were carried out.

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Crystal structures of spleen tyrosine kinase in complex with novel inhibitors: structural insights for design of anticancer drugs

Abstract: The atomic coordinates and structure factors for human SYK are in the Protein Data Bank under accession codes 4XG2 (inhibitor-free form), 4XG3 (G206), 4XG4 (G207), 5GHV (O178), 4XG6 (O194), 4XG7 (O259), 4XG8 (O272), and 4XG9 (O282).

Cited by 10 publications

References 44 publications

Cancer Transcriptome Dataset Analysis: Comparing Methods of Pathway and Gene Regulatory Network-Based Cluster Identification

Cancer Transcriptome Dataset Analysis: Comparing Methods of Pathway and Gene Regulatory Network-Based Cluster Identification

3D-QSAR-Based Pharmacophore Modeling, Virtual Screening, and Molecular Dynamics Simulations for the Identification of Spleen Tyrosine Kinase Inhibitors

Design and Synthesis of Novel Pyrazoles, Pyrazolines, and Pyridines From Chalcone Derivatives With the Assessment of Their in Vitro Anticancer Activity Against T-47d and Uacc-257 Cell Lines

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