Design and screening of FAK, CDK 4/6 dual inhibitors by pharmacophore model, molecular docking, and molecular
Chuance Sun1, Lijun Feng1, Xiaohua Sun1
1College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, China.
Abstract:
Focal adhesion kinase (FAK) is one kind of tyrosine kinases that modulates integrin and growth factor signaling pathways, which is a promising therapeutic target because of involving in the migration, proliferation and survival of cancer cell. Overexpression and amplification of cyclin-dependent kinase 4/6 (CDK4/6) occur in many cancers and may be the cause of resistance to CDK4/6 inhibitors in preclinical models. The latest research shows that the combination of FAK and CDK4/6 can be dually targeted to enhance the antitumor effects. In this study, FAK and CDK4/6 dual target inhibitors were designed by computer-aided drug design. Seven million molecules were screened by the pharmacophore model and molecular docking. Finally, 6 compounds were obtained. Molecular dynamics simulation of compound 1, 2 and 3 showed that it has good binding stability to both receptors. According to the binding modes of compound 1 with two receptors, corresponding modifications were made, and 7 novel designed compounds were obtained. The docking energy of these novel designed compounds were lower than that of compound 1, and they can be tested in future.Communicated by Ramaswamy H. Sarma.
Insights
Researchers designed novel dual inhibitors targeting focal adhesion kinase (FAK) and cyclin-dependent kinase 4/6 (CDK4/6) to enhance antitumor effects. Computer-aided drug design yielded promising compounds with good binding stability for potential cancer therapy.
Area of Science:
- Oncology
- Pharmacology
- Computational Chemistry
Background:
- Focal adhesion kinase (FAK) is a tyrosine kinase crucial for integrin and growth factor signaling, implicated in cancer cell migration, proliferation, and survival.
- Overexpression and amplification of cyclin-dependent kinase 4/6 (CDK4/6) are observed in many cancers and can lead to resistance against CDK4/6 inhibitors.
- Dual targeting of FAK and CDK4/6 presents a promising strategy to enhance antitumor efficacy.
Purpose of the Study:
- To design novel dual inhibitors targeting both FAK and CDK4/6 using computer-aided drug design.
- To evaluate the binding stability and potential therapeutic efficacy of the designed compounds.
Main Methods:
- Screening of seven million molecules using pharmacophore modeling and molecular docking to identify potential dual inhibitors.
- Molecular dynamics simulations were performed on initial lead compounds (1, 2, and 3) to assess binding stability.
- Structure-based modifications of a lead compound (compound 1) were made based on binding mode analysis, leading to the design of new compounds.
Main Results:
- Six compounds were initially identified from the screening process.
- Compounds 1, 2, and 3 demonstrated good binding stability to both FAK and CDK4/6 targets via molecular dynamics simulations.
- The 7 newly designed compounds, based on modifications of compound 1, exhibited improved docking energies compared to the parent compound.
Conclusions:
- The study successfully designed novel dual FAK and CDK4/6 inhibitors with potential for enhanced antitumor activity.
- The designed compounds warrant further in vitro and in vivo testing to validate their therapeutic potential in cancer treatment.
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