Molecular insights into kaempferol derivatives as potential inhibitors for CDK2 in colon cancer: pharmacophore modeling, docking, and dynamic analysis

Cyclin-dependent kinase 2 (CDK2) has been recognized as one of the crucial factors in cell cycle regulation and has been proposed as a potential target for cancer therapies, particularly for colorectal cancer (CRC). Due to the increased incidence rate of CRC and challenges associated with existing treatment options, there is a need for efficient and selective anti-cancer compounds. The current work aims to explore the ability of novel kaempferol derivatives as CDK2 inhibitors by performing conceptual pharmacophore modeling, molecular docking, and molecular dynamic analysis. Kaempferol and its derivatives were obtained from PubChem, and the optimized 3D structures of the compounds were generated using Maestro Ligprep. Subsequently, a pharmacophore model was developed to identify compounds with high fitness values, resulting in the selection of several kaempferol derivatives for further study. We evaluated the ADMET properties of these compounds to assess their therapeutic potential. Molecular docking was conducted using Maestro and BIOVIA Discovery Studio version 4.0 to predict the binding affinities of the compounds to CDK2. The top candidates were subjected to MM-GBSA analysis to predict their binding free energies. Molecular dynamics simulations using GROMACS were performed to assess the thermodynamic stability of the ligand-protein complexes. The results revealed several kaempferol derivatives with high predicted binding affinities to CDK2 and favorable ADMET properties. Specifically, compounds <b>5281642, 5318980,</b> and <b>14427423</b> demonstrated binding free energies of -30.26, -38.66, and -34.2 kcal/mol, respectively. Molecular dynamics simulations indicated that these ligand-protein complexes remained stable throughout the simulation period, with RMSD values remaining below 2 Å. In conclusion, the identified kaempferol derivatives show potential as CDK2 inhibitors based on computational predictions and demonstrate stability in molecular dynamics simulations, suggesting their future application in CRC treatment by targeting CDK2. These computational findings encourage further experimental validation and development of kaempferol derivatives as anti-cancer agents.