Design of 2-amino-6-methyl-pyrimidine benzoic acids as ATP competitive casein kinase-2 (CK2) inhibitors using
S Patel1, S Patel2, K Tulsian1
1Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, India.
Abstract:
Overexpression of casein kinase-2 (CK2) has been implicated in several carcinomas, mainly lung, prostate and acute myeloid leukaemia. The smaller nucleotide pocket compared to related kinases provides a great opportunity to discover newer ATP-competitive CK2 inhibitors. In this study, we have employed an integrated structure- and fragment-based design strategy to design 2-amino-6-methyl-pyrimidine benzoic acids as ATP-competitive CK2 inhibitors. A statistically significant four features-based E-pharmacophore (ARRR) model was used to screen 780,092 molecules. Further, the retrieved hits were considered for molecular docking study to identify essential binding interactions. At the same time, fragment-based virtual screening was performed using a dataset of 1,542,397 fragments. The identified hits and fragments were used as structure templates to rationalize the design of 2-amino-6-methyl-pyrimidine benzoic acids as newer CK2 inhibitors. Finally, the binding interactions of the designed hits were identified using an induced fit docking (IFD) study, and their stability was estimated by a molecular dynamics (MD) simulation study of 100 ns.
Insights
Researchers designed novel 2-amino-6-methyl-pyrimidine benzoic acids as ATP-competitive casein kinase-2 (CK2) inhibitors. This study utilized structure- and fragment-based design strategies to target CK2, a kinase implicated in various carcinomas.
Area of Science:
- Medicinal Chemistry
- Computational Drug Design
- Oncology
Background:
- Overexpression of casein kinase-2 (CK2) is linked to several cancers, including lung, prostate, and acute myeloid leukemia.
- The unique nucleotide pocket of CK2 presents an opportunity for developing targeted ATP-competitive inhibitors.
Purpose of the Study:
- To design novel ATP-competitive CK2 inhibitors using an integrated structure- and fragment-based approach.
- To identify potential therapeutic agents for carcinomas associated with CK2 overexpression.
Main Methods:
- Utilized a four-feature E-pharmacophore model (ARRR) for virtual screening of over 780,000 molecules.
- Performed fragment-based virtual screening on over 1.5 million fragments.
- Employed molecular docking, induced fit docking (IFD), and 100 ns molecular dynamics (MD) simulations to analyze binding interactions and stability.
Main Results:
- Successfully designed 2-amino-6-methyl-pyrimidine benzoic acids as potential CK2 inhibitors.
- Identified key binding interactions and assessed the stability of designed inhibitors through computational studies.
Conclusions:
- The integrated structure- and fragment-based design strategy is effective for discovering novel CK2 inhibitors.
- The designed 2-amino-6-methyl-pyrimidine benzoic acids represent promising candidates for further development as anti-cancer therapeutics targeting CK2.
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