Molecular docking study of Cyclin-dependent kinase 2 with natural flavonolignans towards the treatment of colon cancer
Molecular docking study of Cyclin-dependent kinase 2 with natural flavonolignans towards the treatment of colon cancer
Tooba Abdizadeh,1,*
1. Clinical Biochemistry Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
Introduction: Colorectal cancer is one of the most common cancers worldwide, and it is also one of the major causes of mortality from cancer. Cyclin-dependent kinases (CDKs) are cell cycle regulators, and abnormal activation can accelerate tumor cell proliferation. Therefore, inhibition of CDKs is considered a important therapeutic strategy. This study focused to investigate anti-CDK2 potential of natural flavonolignans using molecular docking approach.
Methods: The molecular docking process was performed using Molecular Operation Environment (MOE) software to predict the mode of interaction between the best possible biological conformations of flavonolignans in the active site of CDK2 enzyme. The 2D structure of flavonolignans including silybin A, silybin B, isosilybin A, isosilybin B, silychristin, isosilychristin, and silydianin were prepared by Chem Draw ultra 8.0 software and converted into PDB format by Hyper Chem7 using AM1 semiempirical method. The flavonolignans were docked into the active site of CDK2 (PDB ID: 2A4L) by MOE software. The best pose of compounds with the higher score was selected for ligand-target interaction analysis by the LigX module in MOE software.
Results: The docking results showed that isosilychristin (−16.71 kcal mol−1) to be the most potent inhibitor of CDK2 as compared to 5-fluorouracil (−6.50 kcal mol−1). Other flavonolignans namely, silybin A (−15.70 kcal mol−1), silybin B (−13.71 kcal mol−1), isosilybin A (−14.50 kcal mol−1), isosilybin B (−15.85 kcal mol−1), silychristin (−14.85 kcal mol−1), and silydianin (−14.90 kcal mol−1) also showed potent inhibition against CDK2, the stability of these molecules with CDK2 was almost more than 5-fluorouracil. According to docking results, flavonolignans bind strongly with some of the amino acid residues in the active site of CDK2 such as Asp86, Lys89, His84, Leu83, Glu81, Lys33 and Leu134.
Conclusion: These results can provide a lead in exploring the flavonolignans in treatment of colon cancer after further studies.