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 really a novel predictive biomarker for immunotherapy in cancer.

Methods: Compounds were in silico modelled by caused fit docking protocol inside a molecular operating atmosphere (MOE, MOE.v.2015). The Three-dimensional (3D) X-ray crystallized structure of CSF1R kinase (Protein Databank, ID 4R7H) was acquired 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 acquired from PubChem Database. These structures were modelled in Amber10:EHT molecular pressure field, and quick prep application was utilized to fix and optimize the structures for missing residues, H-counts, termini capping, and alternates. The binding site was defined inside the vicinity from the co-crystallized ligand of CSF1R kinase. The compounds were docked through the triangular matcher placement method and rated through the London dG scoring function. The docked poses were further refined through the caused fit method. The pose using the cheapest binding score (?G) was utilized to model the ligand interaction profile in Discovery Studio Visualizer v17.2. The co-crystallized ligand was docked in the apo conformation, and root-mean-square deviation was computed to validate the docking protocol.

Results: All 7 CSF1R inhibitors communicate with residue Met637 exhibiting selectivity aside from edicotinib. The inhibitors maintain CSF1R within an auto-inhibitory conformation by getting together with Asp797 from the Asp-Phe-Gly (DFG) motif and/or hindering the conserved salt bridge created between Glu633 and Lys616 thus stabilizing the activation loop, or getting together with tryptophan residue (Trp550) within the juxtamembrane domain. DCC-3014, ARRY-382, BLZ-945, and sorafenib bind using the cheapest binding energy with CSF1R kinase.

Conclusions: Pyrimidines are potent inhibitors that communicate with CSF1R residues. DCC-3014 and ARRY-382 exhibit exceptional pharmaceutical potential exhibiting great structural stability and affinity.