Molecular docking of substituted schiff bases derived from s-benzyldithiocarbazate as potential anticancer agents

• Main Author: How, Fiona Ni Foong
• Format: Conference or Workshop Item
• Language: English
• Published: Frontiers 2018
• Subjects: QD Chemistry
• Online Access: http://irep.iium.edu.my/68776/1/68776_MOLECULAR%20DOCKING%20OF%20SUBSTITUTED%20SCHIFF%20BASES%20DERIVED_complete.pdf; http://irep.iium.edu.my/68776/; https://www.frontiersin.org/10.3389/conf.fphar.2018.63.00100/event_abstract?sname=International_Conference_on_Drug_Discovery_and_Translational_Medicine_2018_(ICDDTM_18)%E2%80%9CSeizing_Op

Background Breast cancer is one of the lethal diseases worldwide. According to the Malaysia National Cancer Registry Report (MNCR 2007-2011), 17.7% from 103,507 new cases of cancer detected throughout Malaysia was breast cancer. The current treatments available are chemotherapy and hormone therapy using tamoxifen. However, it causes some side effects, which includes extreme fatigue, loss appetite, and depression. Therefore, there is a need for more targeted and less side-effect anti-cancer drug. Substituted Schiff bases derived from S-benzyldithiocarbazate are well known for their profound anticancer activity. However, there is no relationship to correlate the structural variation with their anticancer activity. This study served as the very first premier work to uncover the structure-activity relationship of the substituted Schiff bases derived from S-benzyldithiocarbazate. Methods This research sought to predict the binding affinity and molecular interactions that are responsible for the anticancer activity of the bioactive substituted dithiocarbazate derivatives towards estrogen receptor alpha (ERα) through molecular docking study. A total of eight substituted Schiff bases derived from S-benzyldithiocarbazate extracted from previous reported literature and one standard drug, tamoxifen were docked towards onto the crystallised structure of ERα (PDB ID: 3ERT). Results All the eight substituted Schiff bases, S-benzyldithiocarbazate and tamoxifen exhibited good binding affinity towards the receptor ERα ranging from -8.4 to -6.0 kcal/mol. Comparative analysis on the binding interactions of the docked complexes showed that the Schiff bases have different binding interactions with the receptor compared to the standard drug, tamoxifen. Among the Schiff bases, it was observed that the Schiff bases with 5-chloroisatin, 5-fluoroisatin and 5-bromoisatin showed the best binding affinity towards ERα with -8.4, -8.2, -8.1 kcal/mol respectively, exerted good IC50 values ranging from 6.40 to 38.60 µg/mL which was lower than tamoxifen (10.03 µg/mL). The good binding affinities were achieved due to the presence of hydrophobic contacts and hydrogen bonds and between the Schiff bases and amino acid residues of ERα receptor, which were important in forming stable complexes to execute biological changes. From the findings, it was observed that the presence of aromatic rings, halogen, and nitrogen, functional groups in the chain of substituted Schiff bases dithiocarbazate derivatives greatly affect the binding affinity. Conclusion This study demonstrated that molecular docking can be utilised to recognize the relationship between Schiff bases dithiocarbazate derivatives and their anti-cancer activities. It can also be concluded that the Schiff bases with specific chemical substituents could serve as a lead compound and be developed as a potential anticancer agent. It is expected that this relationship can be utilized for the development of anticancer drugs with improved selectivity, effectiveness and efficacy. Acknowledgements The authors appreciated RIGS15-018-0018 for financial assistance.