Evaluating the Therapeutic Potential of Curcumin and Synthetic Derivatives: A Computational Approach to Anti-Obesity Treatments

Marakiya T Moetlediwa; Babalwa U Jack; Sithandiwe E Mazibuko-Mbeje; Carmen Pheiffer; Salam J J Titinchi; Elliasu Y Salifu; Pritika Ramharack

doi:10.3390/ijms25052603

Evaluating the Therapeutic Potential of Curcumin and Synthetic Derivatives: A Computational Approach to Anti-Obesity Treatments

Int J Mol Sci. 2024 Feb 23;25(5):2603. doi: 10.3390/ijms25052603.

Authors

Marakiya T Moetlediwa^{1

2}, Babalwa U Jack¹, Sithandiwe E Mazibuko-Mbeje², Carmen Pheiffer^{1

3}, Salam J J Titinchi⁴, Elliasu Y Salifu¹, Pritika Ramharack^{1

5}

Affiliations

¹ Biomedical Research and Innovation Platform, South African Medical Research Council, Tygerberg 7505, South Africa.
² Department of Biochemistry, North-West University, Mmabatho 2745, South Africa.
³ Department of Obstetrics and Gynaecology, Faculty of Health Sciences, University of Pretoria, Pretoria 0001, South Africa.
⁴ Department of Chemistry, Faculty of Natural Science, University of the Western Cape, Bellville 7535, South Africa.
⁵ Pharmaceutical Sciences, School of Health Sciences, University of KwaZulu-Natal, Westville, Durban 4001, South Africa.

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.

Keywords: curcumin; obesity; pharmacodynamics; pharmacokinetics; synthetic curcumin derivatives.

MeSH terms

Curcumin* / pharmacology
Cyclooxygenase 2 / metabolism
Humans
Molecular Docking Simulation
Molecular Dynamics Simulation
Obesity
PPAR gamma / metabolism

Substances

Curcumin
PPAR gamma
Cyclooxygenase 2

Grants and funding

This research was funded by the South African Medical Research Council (SAMRC) biomedical and research innovation platform (BRIP) and the NRF Thuthuka Programme (Grant Number: 129508) awarded to Babalwa Jack.