Discovery of Structural Prospects of Imidazo[1,5-a]pyrazine Derivatives as BTK Inhibitors Against Cancer: A Computational Study

Background: Bruton's tyrosine kinase (BTK) plays an important role in cell development and proliferation. BTK inhibitors are encouraging novel agents against B-cell malignancies and autoimmune diseases. Although BTK inhibitors have been approved by the FDA to lower off-target effects and reduce emerging resistances, it is necessary to develop novel BTK inhibitors with better outcomes and minimum side effects. Objective: The present study includes pharmacophore hypothesis, 3D QSAR, virtual screening, docking, ADME analysis, and screening of potential imidazo[1,5-a]pyrazine derivatives as BTK inhibitors. Methods: Generation of pharmacophore hypothesis, virtual screening, 3D QSAR, molecular docking, and ADME analysis were conducted. Results: The pharmacophore study generated 20 pharmacophore hypotheses as BTK inhibitors. The five-point hypothesis DPRRR_1 was selected, consisting of one hydrogen bond donor, one positive ionic, and three-ring aromatic features. 3D QSAR study of the compounds provided the best model with high Q(2) (0.8683), R-2 (0.983), and (RCV)-C-2 (0.5338) values. The developed pharmacophore model was further taken for screening of ZINC database ligands for evaluation of docking interaction and physiochemical properties. Potent compounds of the series 15, 27, 8n, and 38 showed good docking scores -8.567 -7.465 -6.922 -6.137 respectively. Conclusion: All the pharmacokinetic parameters analyzed, including human oral absorption of active compounds of the series, were found to be within the permissible range. The present geometry and features included in the pharmacophore hypothesis can be used for the development of novel BTK inhibitors as anticancer agents.

Automated summary

BTK inhibitors play a crucial role in cell development and proliferation, being potential agents against B-cell malignancies and autoimmune diseases. This study focused on developing novel BTK inhibitors through pharmacophore hypothesis, 3D QSAR, virtual screening, docking, and ADME analysis. The pharmacophore study identified 20 hypotheses, with the DPRRR_1 hypothesis showing promising features. QSAR study provided a strong model, and screening yielded potent compounds with good docking scores.