Structure-based design of alicyclic fused pyrazole derivatives for targeting TGF-β receptor I kinase: molecular
Natarajan Saravanakumar1, Arunagiri Sivanesan Aruna Poorani1, Ganesapandian Latha1,2
1Supramolecular and Catalysis Lab, Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai, Tamil Nadu, India.
Abstract:
TGF-β receptor I kinase plays a significant role in cancer biology and is a well-established target for cancer drug development, as evidenced by active molecules like Galunisertib (LY2157229). Computational studies were conducted to analyse the catalytic site of TGF-β receptor I kinase, identifying key amino acid residues essential for binding. Based on these findings, Alicyclic fused pyrazole derivatives were designed. The target molecules were synthesized through a multi-step process, with an important intermediate obtained via Suzuki coupling, followed by various ligand and catalyst optimizations. A total of thirteen molecules were synthesized by optimizing temperature, solvent, and base. After characterization, the synthesized, Alicyclic fused pyrazole derivatives were screened for TGF-β receptor I kinase inhibition and in vitro cytotoxic activity. To further elucidate their binding mechanism, molecular docking and molecular dynamics studies were performed. The most active compound 16c, was subjected to in silico ADME screening, which revealed a favorable pharmacokinetic profile. Molecular Dynamics simulation study indicated that specific aminoacid residue interaction with TGF-β receptor I kinase. Additionally, DFT calculations were conducted on the active molecules to gain deeper insights into their electronic properties, supporting their potential as effective anticancer agents.
Insights
Researchers designed novel alicyclic fused pyrazole derivatives targeting TGF-β receptor I kinase for cancer therapy. The most potent compound demonstrated promising anticancer activity and favorable pharmacokinetics, suggesting therapeutic potential.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Computational Chemistry
Background:
- Transforming growth factor-beta (TGF-β) receptor I kinase is a crucial target in cancer drug development.
- Existing therapies highlight the significance of targeting this kinase pathway.
Purpose of the Study:
- To design, synthesize, and evaluate novel alicyclic fused pyrazole derivatives as TGF-β receptor I kinase inhibitors.
- To investigate the binding mechanism and pharmacokinetic properties of potential anticancer agents.
Main Methods:
- Computational analysis of the TGF-β receptor I kinase catalytic site.
- Multi-step synthesis of alicyclic fused pyrazole derivatives, including Suzuki coupling.
- In vitro kinase inhibition and cytotoxicity assays.
- Molecular docking, molecular dynamics, and DFT calculations.
- In silico ADME screening.
Main Results:
- Thirteen novel alicyclic fused pyrazole derivatives were synthesized and characterized.
- Compound 16c exhibited significant TGF-β receptor I kinase inhibition and in vitro cytotoxic activity.
- Molecular simulations elucidated key binding interactions and favorable pharmacokinetic properties for compound 16c.
- DFT calculations provided insights into the electronic properties of active compounds.
Conclusions:
- Alicyclic fused pyrazole derivatives represent a promising class of TGF-β receptor I kinase inhibitors.
- Compound 16c shows potential as an effective anticancer agent due to its inhibitory activity and favorable ADME profile.
- Further studies are warranted to explore the therapeutic application of these compounds in cancer treatment.
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