Molecular Docking and Dynamic Studies of Chlorogenic Acid Isomers as Antagonists of p53 Transcription Factor for Potential Adjuvant Radiotherapy.

OBJECTIVE

Chlorogenic acids (CGAs) are among potential natural radioprotectant for inhibiting inappropriate p53 activation of adjacent normal tissues upon radiotherapy. However, previous studies are mainly focused on 5-O-caffeoylquinic acid (5CGA). In this study, the antagonist role of three CGAs isomers against p53 protein is assed for potential anti-apoptotic activity using molecular docking and dynamic experiments.

METHODS

The physicochemical and pharmacokinetic profile three CGA isomers (3-O-caffeoylquinic acid (3CGA), 4-O-caffeoylquinic acid (4CGA), and 5CGA) were predicted using SwissADME web. Subsequently, they were subjected to docking using AutoDock software against to p53's L1/S3 pocket. The best binding pose was advanced to molecular dynamic (MD) simulation spanning 5 ns to evaluate the time dependent stability using Visual Dynamic web.

RESULTS

The SwissADME prediction showed that the position of esterification on quinic moiety had no impact on the physicochemical and pharmacokinetic of CGA isomers. They only violated one out of five Lipinski's rules with the Abbot's bioavailability score of 0.11. The docking results revealed that the 4CGA has the highest binding energy (-5.41 kCal/mol) on L1/S3 pocket of p53 protein followed by 5CGA (-4.81 kCal/mol) and 3CGA (-4.62 kCal/mol). The MD simulation showed that the p53 complex with each CGA isomers had a root mean square deviation of less than 0.25 nm and a radius gyration that of close to reference apoprotein. Importantly, fluctuation of important residues at L1/S3 pocket was decrease through complex formation with 3CGA (at His155 and Ser121) and 4CGA (Lys120 and Ser121).

CONCLUSION

The CGA isomers satisfy the drug-likeness for a potential oral medicine. They potentially play role as anti-apoptotic agent through binding with p53's pocket that involves in DNA transcriptional activity. Among them, the 4CGA possess the highest potential due to its highest free binding affinity and its ability to stabilize the residues fluctuation in L1/S3 pocket.