Pharmacophore based High Throughput Virtual Screening towards the Discovery of Novel BLK (B-lymphocyte kinase)- tyrosine Kinase Inhibitors

Abstract

Abstract: Aim: LK (B-lymphocyte kinase) is a protein from the family SRC (Proto-oncogene tyrosine-protein kinase), an important cell signaling molecule that influences cellular response. The BLK tyrosine-protein kinase has been a potential target for cancer therapy. As a result, this could be an initial step toward the development of novel inhibitors to fight cancer. Materials and Methods: A homology model of human BLK tyrosine kinase was constructed using Phyre2. Active site prediction was done for the model using the CASTp server. High Throughput virtual screening was performed with the help of a ligand-based pharmacophore model of FDA (Food and Drug Administration) approved SRC tyrosine family kinase inhibitors using the PharmaGist and ZINCPharmer servers. The 250 novel compounds obtained were docked by a Python script-based method with Autodock Vina. To ensure drug safety, ADME/Tox (Absorption, Distribution, Metabolism, Elimination, Toxicity) analysis was performed for the molecules with the lowest binding energy. Six compounds that passed ADME/Tox analysis were again utilized to perform molecular docking with Autodock4. The active residues were then identified using PLIP [protein ligand interaction profiler]. Results and Conclusion: Six compounds passed ADME/Tox analysis. Based on the molecular docking analysis, the compound ZINC57306994 showed an increased binding affinity with the target BLK tyrosine kinase. The compound ZINC57306994 may serve as a lead molecule that could be developed into a potent BLK tyrosine kinase inhibitor. Keywords: Pharmacophore modeling, Molecular docking, BLK tyrosine kinase, Cancer.