Computational analysis of protein-ligand interaction by targeting a cell cycle restrainer
Rahul Singh1, Rituraj Purohit1
1Structural Bioinformatics Lab, CSIR-Institute of Himalayan Bioresource Technology (CSIR-IHBT), Palampur, HP 176061, India; Biotechnology Division, CSIR-IHBT, Palampur, HP 176061, India; Academy of Scientific & Innovative Research (AcSIR), Ghaziabad 201002, India.
Background And Objective:
The cyclin-dependent kinases 4/6 (CDK4/6) are among the most crucial controllers of the cell cycle, and their abnormal activity may induce uncontrolled cell multiplication, leading to cancers. The FDA currently approved three CDK4/6 inhibitors, however, they are associated with a variety of side effects. Thus it is required to design/develop novel potent and safe CDK4/6 inhibitors.
Methods:
In the present work, we furnished an integrated in-silico approach followed by steered molecular dynamics (SMD) simulations to identify molecules that can be developed into novel CDK4/6 inhibitors.
Results:
Out of thirty-two 3-methyleneisoindolin-1-one molecules we selected top three M18, M24, and M32 molecules as potential drug candidates based on their respective interaction energies. According to the robust 250 ns MD simulations and thermodynamic free energy, M24 was the best molecule in comparison to palbociclib. In SMD, M24 required ∼205.587 kJ/mol/nm external pulling force, while palbociclib needed ∼160.97 kJ/mol/nm to dissociate from the binding pocket of the CDK4.
Conclusions:
The high pulling force required for M24 dissociation from the binding site denotes stronger binding with CDK4. Therefore, M24 offers the possibility of a critical starting structure in developing effective CDK4 inhibitors.
Insights
Researchers identified M24 as a promising novel inhibitor for cyclin-dependent kinases 4/6 (CDK4/6), a key target in cancer therapy. This molecule demonstrated stronger binding affinity to CDK4 than the existing drug palbociclib, offering potential for safer cancer treatments.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinases 4/6 (CDK4/6) regulate the cell cycle; aberrant CDK4/6 activity drives cancer progression.
- Current FDA-approved CDK4/6 inhibitors cause side effects, necessitating the development of novel, safer alternatives.
Purpose of the Study:
- To identify and evaluate novel potent and safe CDK4/6 inhibitors using an integrated in-silico approach.
- To explore the potential of 3-methyleneisoindolin-1-one derivatives as therapeutic agents against CDK4/6.
Main Methods:
- Utilized an integrated in-silico strategy combined with steered molecular dynamics (SMD) simulations.
- Evaluated thirty-two 3-methyleneisoindolin-1-one molecules for their binding affinity and stability with CDK4.
Main Results:
- Identified M18, M24, and M32 as top drug candidates based on interaction energies.
- M24 exhibited superior binding to CDK4 compared to palbociclib in 250 ns MD simulations and free energy calculations.
- SMD simulations showed M24 required a higher pulling force (~205.587 kJ/mol/nm) for dissociation from CDK4 than palbociclib (~160.97 kJ/mol/nm).
Conclusions:
- The substantial pulling force for M24's dissociation indicates a stronger binding interaction with CDK4.
- M24 serves as a promising lead structure for the development of more effective and potentially safer CDK4 inhibitors for cancer therapy.
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