DOCKING STUDIES OF CURCUMIN ANALOGS AGAINST METHIONINE AMINOPETIDASE 2 AND BIOLOGICAL EVALUATION OF LEAD MOLECULES IN COLON CELLS
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Colorectal cancer is one of the major causes of death worldwide. In Canada, colon cancer is the third most commonly diagnosed cancer. Fortunately, 90% of deaths and cases of colon cancer are preventable. If detected at an early stage, it can be cured. There are different challenges in developing a drug for cancer treatments which include tumor selectivity, target specificity, drug efficacy, and overcoming multi-drug resistance (MDR). Designing target specific molecules has brought better success in developing new anticancer agents. Various anticancer targets have been explored for this purpose. Among them, metalloproteinases such as methionine aminopeptidase 2 (MetAP2) play a major role in being an anticancer drug target. This research focuses on the investigation of novel curcumin analogs displaying both MetAP2 inhibitory and cytotoxic properties for further development as anticancer agents. The purpose of this study is to identify promising cytotoxic curcumin analogs as inhibitors of MetAP2 expression and investigate their potential as novel anticancer drug candidates. The compounds were selected from docking studies against the enzyme MetAP2. They were evaluated for their physicochemical properties through SwissADME scores. The best compounds among the screened compounds were then considered for preclinical evaluations through screening against the colon cancer cell lines HCT116, and HT29, and the normal colon cell line CRL1790 in vitro for their cytotoxic profiles. The best 2 compounds (NC 1768 and NC 1773) were analysed for their inhibitory property against MetAP2 expression in the HT29 cell line using Western blot analysis. The Student’s t-test for paired data and Dunnett’s post hoc test with p<0.05 were performed using the program IBM SPSS Statistics 26. One hundred thirty compounds were docked against MetAP2 enzyme, out of these the top 10 compounds that showed good results for their physicochemical properties assessment were taken for cytotoxic evaluation. Among the 10 compounds, 2 compounds (NC 1768 and NC 1773) had good IC50 profiles, and they were analysed using Western blot. The Western blot indicated that protein expression was reduced for NC 1773 against HT29 cell line. The statistical analysis performed using Student’s t-test for paired data was not significant with p>0.05 in all 3 bivariate linear models. Dunnett’s post hoc test showed significance at p<0.05 for the treatment protocol of NC 1773 in comparison with control (cells with absence of treatment). The compound NC 1773 has shown excellent results in docking and Western blot analysis. The Western blot indicated that protein expression was reduced for NC 1773 against HT29 cell line. Dunnett’s post hoc test showed significance at p<0.05 for the treatment protocol of NC 1773 in comparison to control (cells with absence of treatment). It has an ideal IC50 profile and predicted bioavailability which warrants further investigation for the mechanism of action.
DegreeMaster of Science (M.Sc.)
DepartmentPharmacy and Nutrition
SupervisorDimmock, Jonathan R.; Sharma, Rajendra K.
CommitteeDadachova, Ekaterina; Bandy, Brian; Tikoo, Suresh K.; Wu, Yuliang
Copyright DateJune 2021
Methionine aminopeptidase 2 (MetAP2)
anticancer drug candidates