Identification of selective plant-derived natural carotenoid and flavonoids as the potential inhibitors of DHHC-mediated protein S-palmitoylation: an in silico study

Abstract

Protein S-palmitoylation mediated by DHHCs is recognized as a distinct and reversible form of lipid modification connected with several health perturbations, including neurodegenerative disorders, cancer, and autoimmune conditions. However, the pharmacological characteristics of current pan-DHHC inhibitors, particularly their toxicity and off-target effects, have hindered their in-depth cellular investigations. The therapeutic properties of the natural compounds, with minimal side effects, allowed us to evaluate them as DHHC-targeting inhibitors. Here, we performed an insilico screening of 115 phytochemicals to assess their interactions with the DHHC20 binding site. Among these compounds, lutein, 5-hydroxyflavone, and 6-hydroxyflavone exhibited higher binding energy (−9.2, −8.5, and −8.5 kcal/mol) in the DHHC20 groove compared to pan-DHHC inhibitor 2-BP (−7.0 kcal/mol). Furthermore, we conducted a 100 ns MD simulation to evaluate the stability of these complexes under physiological conditions. The MDsimulation results indicated that DHHC20 formed a more stable conformation with lutein compared to 5-hydroxyflavone and 6-hyroxyflavone via hydrophobic and H-bond interactions. Conclusively, these results could serve as a promising starting point for exploring the use of these natural molecules as DHHC20 inhibitors.

Communicated by Ramaswamy H. Sarma

Keywords:

• DHHCs
• molecular docking
• MM-GBSA
• flavonoids
• MD-simulation
• DHHC20 inhibitors

Author contributions

S.C. collected the data and wrote the manuscript. N.P. edited the manuscript. S.S. and A.S. supported, managed, and supervised the manuscript.

Acknowledgment

We are thankful to all members of Sushabhan Sadhukhan and Avinash Sonawane laboratories for their valuable discussions.

Consent for publication

All authors approved the final manuscript for submission.

Disclosure statement

The authors declare no competing interest.

Additional information

Funding

The authors gratefully acknowledge the financial support from the Indian Institute of Technology Indore and Indian Institute of Technology Palakkad for the provision of conducting research and DST, Govt. of India, for providing fellowship under the INSPIRE Fellowship Scheme (DST/INSPIRE Fellowship/2018/IF180022) to Suchi Chaturvedi.