Title:Discovery of Structural Prospects of Imidazo[1,5-a]pyrazine Derivatives as BTK Inhibitors Against Cancer: A Computational Study
Volume: 18
Issue: 12
Author(s): Amena Ali*, Abuzer Ali and Mohamed Jawed Ahsan
Affiliation:
- Department of Pharmaceutical Chemistry, College of Pharmacy, Taif University, P.O. Box 11099, Taif, 21944,Saudi Arabia
Keywords:
Bruton's tyrosine kinase, BTK inhibitors, B-cell malignancy, 3D QSAR, docking, virtual screening, ADME
analysis.
Abstract:
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 Q2 (0.8683), R2 (0.983), and R2CV (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.