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<p>BTK (Bruton’s tyrosine kinase) is a cytoplasmic, non-receptor tyrosine kinase which belongs to tec family of kinases and has significant role in B-cell malignancies. It plays a vital role in B-cell signalling, cell proliferation and signal transduction. To address this issue, several BTK inhibitors have been synthesized, but new molecules are needed to overcome off-target effects, enhance selectivity and combat resistance. In his study, we have used LBDD (Ligand based drug design) approach to screen large databases like NCI, Zinc, ChEMBL, Maybridge and Asinex. The hits obtained from these databases were used to design a new scaffold. The multiple substitution of the scaffold provided a library of compounds. These compounds were docked against BTK protein (PDB ID: 5P9M) in SP (standard precision) mode initially. The selected molecules with docking score less than −&#xa0;8.0 were then docked using XP (extra precision) mode. Docking score for RUPP_27 and RUPP_29 was found to be −&#xa0;7.204 and −&#xa0;6.855 respectively. Both of the molecules exhibited strong protein interaction by forming 2 and 1 hydrogen bonds respectively. The best docked molecule RUPP_27 was subjected to MD analysis simulation study for 100&#xa0;ns and the complex indicated a favorable binding affinity and long-term occupancy of the ligand in the binding pocket.</p> Graphical abstract <p></p>

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Ligand-based design of BTK inhibitors for B cell malignancy: pharmacophore mapping, virtual screening, molecular docking and molecular dynamics simulation analysis

  • 期刊论文

  • 发表日期：

    2026年5月14日

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  • Ruchi S. Pathak,
  • Saumya Patel,
  • Nandan Dixit,
  • Paresh K. Patel

摘要

BTK (Bruton’s tyrosine kinase) is a cytoplasmic, non-receptor tyrosine kinase which belongs to tec family of kinases and has significant role in B-cell malignancies. It plays a vital role in B-cell signalling, cell proliferation and signal transduction. To address this issue, several BTK inhibitors have been synthesized, but new molecules are needed to overcome off-target effects, enhance selectivity and combat resistance. In his study, we have used LBDD (Ligand based drug design) approach to screen large databases like NCI, Zinc, ChEMBL, Maybridge and Asinex. The hits obtained from these databases were used to design a new scaffold. The multiple substitution of the scaffold provided a library of compounds. These compounds were docked against BTK protein (PDB ID: 5P9M) in SP (standard precision) mode initially. The selected molecules with docking score less than − 8.0 were then docked using XP (extra precision) mode. Docking score for RUPP_27 and RUPP_29 was found to be − 7.204 and − 6.855 respectively. Both of the molecules exhibited strong protein interaction by forming 2 and 1 hydrogen bonds respectively. The best docked molecule RUPP_27 was subjected to MD analysis simulation study for 100 ns and the complex indicated a favorable binding affinity and long-term occupancy of the ligand in the binding pocket.

Graphical abstract