Exploring multi-target inhibitors using in silico approach targeting cell cycle dysregulator-CDK proteins

Area of Science:

• Biochemistry and Molecular Biology
• Pharmacology and Drug Discovery
• Computational Chemistry

Background:

• Cyclin-dependent kinases (CDKs) are crucial regulators of cell cycle, transcription, and proliferation.
• CDK dysregulation is implicated in various diseases, notably cancer, making them significant drug targets.
• Developing selective inhibitors for the highly conserved ATP-binding site across CDK family members presents a major challenge.

Purpose of the Study:

• To identify selective inhibitors targeting the ATP-binding site of CDK1, CDK2, CDK4, and CDK5 using a multi-target drug design approach.
• To computationally screen and validate potential drug candidates through molecular docking, molecular dynamics, and binding free energy calculations.
• To elucidate the mechanistic basis of inhibitor binding and identify key residues involved in drug retention.

Main Methods:

• Multi-target drug design strategy.
• Molecular docking simulations to screen a library of drug-like compounds against CDK proteins.
• Molecular dynamics (MD) simulations (6 μs total) and MMPBSA/MMGBSA calculations to assess binding affinity and stability.
• Analysis of root-mean-square deviation (RMSD) and root-mean-square fluctuation (RMSF) to understand conformational changes.

Main Results:

• Identification of five potential selective inhibitors for CDK1, CDK2, CDK4, and CDK5.
• Binding free energies (ΔGbind-PB) for identified inhibitors ranged from -18.24 to -28.43 Kcal/mol.
• Key residues (e.g., Lys33, Asp127, Asp145) and active site regions critical for inhibitor binding were identified.
• LIG3 and LIG4 emerged as the most promising inhibitors based on binding energy, interaction patterns, and stability within the active pocket.

Conclusions:

• The study successfully identified potent competitive inhibitors for the ATP-binding site of CDK proteins using advanced computational techniques.
• The findings provide a foundation for multi-target drug design strategies against CDK-related diseases.
• The identified inhibitors, particularly LIG3 and LIG4, represent promising leads for developing novel therapeutics for cancer and other CDK-associated conditions.