In silico targeting of colony-stimulating factor-1 receptor: delineating immunotherapy in cancer
Aim: Delineate structure-based inhibition of colony-stimulating factor-1 receptor (CSF1R) by small molecule CSF1R inhibitors in clinical development for target identification and potential lead optimization in cancer therapeutics since CSF1R is a novel predictive biomarker for immunotherapy in cance...
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| Format: | Article |
| Language: | English |
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Open Exploration Publishing Inc.
2023-08-01
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| Series: | Exploration of Targeted Anti-tumor Therapy |
| Subjects: | |
| Online Access: | https://www.explorationpub.com/Journals/etat/Article/1002164 |
| _version_ | 1797691632433233920 |
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| author | Zahra Azhar Richard P. Grose Afsheen Raza Zohaib Raza |
| author_facet | Zahra Azhar Richard P. Grose Afsheen Raza Zohaib Raza |
| author_sort | Zahra Azhar |
| collection | DOAJ |
| description | Aim: Delineate structure-based inhibition of colony-stimulating factor-1 receptor (CSF1R) by small molecule CSF1R inhibitors in clinical development for target identification and potential lead optimization in cancer therapeutics since CSF1R is a novel predictive biomarker for immunotherapy in cancer. Methods: Compounds were in silico modelled by induced fit docking protocol in a molecular operating environment (MOE, MOE.v.2015). The 3-dimensional (3D) X-ray crystallized structure of CSF1R kinase (Protein Databank, ID 4R7H) was obtained from Research Collaboratory for Structural Bioinformatics (RSCB) Protein Databank. The 3D conformers of edicotinib, DCC-3014, ARRY-382, BLZ-945, chiauranib, dovitinib, and sorafenib were obtained from PubChem Database. These structures were modelled in Amber10:EHT molecular force field, and quick prep application was used to correct and optimize the structures for missing residues, H-counts, termini capping, and alternates. The binding site was defined within the vicinity of the co-crystallized ligand of CSF1R kinase. The compounds were docked by the triangular matcher placement method and ranked by the London dG scoring function. The docked poses were further refined by the induced fit method. The pose with the lowest binding score (ΔG) was used to model the ligand interaction profile in Discovery Studio Visualizer v17.2. The co-crystallized ligand was docked in its apo conformation, and root-mean-square deviation was computed to validate the docking protocol. Results: All 7 CSF1R inhibitors interact with residue Met637 exhibiting selectivity except for edicotinib. The inhibitors maintain CSF1R in an auto-inhibitory conformation by interacting with Asp797 of the Asp-Phe-Gly (DFG) motif and/or hindering the conserved salt bridge formed between Glu633 and Lys616 thus stabilizing the activation loop, or interacting with tryptophan residue (Trp550) in the juxtamembrane domain. DCC-3014, ARRY-382, BLZ-945, and sorafenib bind with the lowest binding energy with CSF1R kinase. Conclusions: Pyrimidines are potent inhibitors that interact with CSF1R residues. DCC-3014 and ARRY-382 exhibit exceptional pharmaceutical potential exhibiting great structural stability and affinity. |
| first_indexed | 2024-03-12T02:16:01Z |
| format | Article |
| id | doaj.art-4c987951c077468e85c75acd709fab33 |
| institution | Directory Open Access Journal |
| issn | 2692-3114 |
| language | English |
| last_indexed | 2024-03-12T02:16:01Z |
| publishDate | 2023-08-01 |
| publisher | Open Exploration Publishing Inc. |
| record_format | Article |
| series | Exploration of Targeted Anti-tumor Therapy |
| spelling | doaj.art-4c987951c077468e85c75acd709fab332023-09-06T08:01:45ZengOpen Exploration Publishing Inc.Exploration of Targeted Anti-tumor Therapy2692-31142023-08-014472774210.37349/etat.2023.00164In silico targeting of colony-stimulating factor-1 receptor: delineating immunotherapy in cancerZahra Azhar0https://orcid.org/0000-0001-8152-5586Richard P. Grose1https://orcid.org/0000-0002-4738-0173Afsheen Raza2https://orcid.org/0000-0002-8462-2880Zohaib Raza3https://orcid.org/0000-0001-7789-4530Centre of Tumour Biology, Barts Cancer Institute, Queen Mary University of London, EC1M 6BQ London, UKCentre of Tumour Biology, Barts Cancer Institute, Queen Mary University of London, EC1M 6BQ London, UKDepartment of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi 59911, United Arab EmiratesDepartment of Chemistry, The University of Adelaide, 5005 Adelaide, South Australia, AustraliaAim: Delineate structure-based inhibition of colony-stimulating factor-1 receptor (CSF1R) by small molecule CSF1R inhibitors in clinical development for target identification and potential lead optimization in cancer therapeutics since CSF1R is a novel predictive biomarker for immunotherapy in cancer. Methods: Compounds were in silico modelled by induced fit docking protocol in a molecular operating environment (MOE, MOE.v.2015). The 3-dimensional (3D) X-ray crystallized structure of CSF1R kinase (Protein Databank, ID 4R7H) was obtained from Research Collaboratory for Structural Bioinformatics (RSCB) Protein Databank. The 3D conformers of edicotinib, DCC-3014, ARRY-382, BLZ-945, chiauranib, dovitinib, and sorafenib were obtained from PubChem Database. These structures were modelled in Amber10:EHT molecular force field, and quick prep application was used to correct and optimize the structures for missing residues, H-counts, termini capping, and alternates. The binding site was defined within the vicinity of the co-crystallized ligand of CSF1R kinase. The compounds were docked by the triangular matcher placement method and ranked by the London dG scoring function. The docked poses were further refined by the induced fit method. The pose with the lowest binding score (ΔG) was used to model the ligand interaction profile in Discovery Studio Visualizer v17.2. The co-crystallized ligand was docked in its apo conformation, and root-mean-square deviation was computed to validate the docking protocol. Results: All 7 CSF1R inhibitors interact with residue Met637 exhibiting selectivity except for edicotinib. The inhibitors maintain CSF1R in an auto-inhibitory conformation by interacting with Asp797 of the Asp-Phe-Gly (DFG) motif and/or hindering the conserved salt bridge formed between Glu633 and Lys616 thus stabilizing the activation loop, or interacting with tryptophan residue (Trp550) in the juxtamembrane domain. DCC-3014, ARRY-382, BLZ-945, and sorafenib bind with the lowest binding energy with CSF1R kinase. Conclusions: Pyrimidines are potent inhibitors that interact with CSF1R residues. DCC-3014 and ARRY-382 exhibit exceptional pharmaceutical potential exhibiting great structural stability and affinity.https://www.explorationpub.com/Journals/etat/Article/1002164cancer drug developmenttyrosine kinase inhibitorsdrug resistancecomputational modellingmolecular dockingtarget identificationlead optimizationtargeted cancer therapy |
| spellingShingle | Zahra Azhar Richard P. Grose Afsheen Raza Zohaib Raza In silico targeting of colony-stimulating factor-1 receptor: delineating immunotherapy in cancer Exploration of Targeted Anti-tumor Therapy cancer drug development tyrosine kinase inhibitors drug resistance computational modelling molecular docking target identification lead optimization targeted cancer therapy |
| title | In silico targeting of colony-stimulating factor-1 receptor: delineating immunotherapy in cancer |
| title_full | In silico targeting of colony-stimulating factor-1 receptor: delineating immunotherapy in cancer |
| title_fullStr | In silico targeting of colony-stimulating factor-1 receptor: delineating immunotherapy in cancer |
| title_full_unstemmed | In silico targeting of colony-stimulating factor-1 receptor: delineating immunotherapy in cancer |
| title_short | In silico targeting of colony-stimulating factor-1 receptor: delineating immunotherapy in cancer |
| title_sort | in silico targeting of colony stimulating factor 1 receptor delineating immunotherapy in cancer |
| topic | cancer drug development tyrosine kinase inhibitors drug resistance computational modelling molecular docking target identification lead optimization targeted cancer therapy |
| url | https://www.explorationpub.com/Journals/etat/Article/1002164 |
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