Abstract:
Natural compounds such as curcumin, a polyphenolic compound derived from the rhizome
of turmeric, have gathered remarkable scientific interest due to their diverse metabolic benefits
including anti-obesity potential. However, curcumin faces challenges stemming from its unfavorable
pharmacokinetic profile. To address this issue, synthetic curcumin derivatives aimed at enhancing
the biological efficacy of curcumin have previously been developed. In silico modelling techniques
have gained significant recognition in screening synthetic compounds as drug candidates. Therefore,
the primary objective of this study was to assess the pharmacokinetic and pharmacodynamic characteristics
of three synthetic derivatives of curcumin. This evaluation was conducted in comparison to
curcumin, with a specific emphasis on examining their impact on adipogenesis, inflammation, and
lipid metabolism as potential therapeutic targets of obesity mechanisms. In this study, predictive toxicity
screening confirmed the safety of curcumin, with the curcumin derivatives demonstrating a safe
profile based on their LD50 values. The synthetic curcumin derivative 1A8 exhibited inactivity across
all selected toxicity endpoints. Furthermore, these compounds were deemed viable candidate drugs
as they adhered to Lipinski’s rules and exhibited favorable metabolic profiles. Molecular docking
studies revealed that both curcumin and its synthetic derivatives exhibited favorable binding scores,
whilst molecular dynamic simulations showed stable binding with peroxisome proliferator-activated
receptor gamma (PPARγ), csyclooxygenase-2 (COX2), and fatty acid synthase (FAS) proteins. The
binding free energy calculations indicated that curcumin displayed potential as a strong regulator of
PPARγ (−60.2 ± 0.4 kcal/mol) and FAS (−37.9 ± 0.3 kcal/mol), whereas 1A8 demonstrated robust
binding affinity with COX2 (−64.9 ± 0.2 kcal/mol). In conclusion, the results from this study suggest
that the three synthetic curcumin derivatives have similar molecular interactions to curcumin with
selected biological targets. However, in vitro and in vivo experimental studies are recommended to
validate these findings.
