Probing intermolecular interactions and binding stability of kaempferol, quercetin and resveratrol derivatives with PPAR-γ: docking, molecular dynamics and MM/GBSA approach to reveal potent PPAR- γ agonist against cancer

Abstract

Peroxisome Proliferator-Activated Receptors-γ (PPAR-γ), a ligand-activated transcription factor, suggested having anti-inflammatory effects by activating the target genes when bound to the ligand. Herein, we examined a conformational analysis of 8708 derivatives of Kaempferol, Quercetin, and Resveratrol, the prime activators of PPAR-γ molecular target by employing molecular docking and dynamic simulation pipeline to screen out potential agonists. The structure-based docking procedure performed by FlexX tool shortlisted high binding affinities of these derivatives of Kaempferol, Quercetin and Resveratrol with the protein receptor with a score of −38.94 kcal/mol (4'-Carboxy-5, 7-Dihydroxyflavone-CDHF), −41.63 kcal/mol (Demethyltorosaflavone D- DMTF) and −31.52 kcal/mol (Resveratrol-O-disulphate- RD) respectively, signifying the selected derivatives forms interactions like H-bond, Aromatic H-Bond, Pi-Pi stacking and salt bridges with PPAR-γ. The PPAR-γ-derivative complex was stabilized by intermolecular hydrogen bonds and stacking interactions. A greater interaction was significantly observed between the binding affinities of derivatives compared to the standards. Based on the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) carried by the means of high-speed molecular dynamics (MD) and simulation of best-docked poses, the ligand, DMTF attained the most favored interaction with PPAR-γ. Thus, it appeared to have high chemical scaffold diversity and may confer high drug-likeness. The binding free energy (ΔG) led us to manifest Quercetin derivative to have a key role for PPAR-γ receptor. The result obtained clearly indicates the exploitation of the promising new drug leads that may further influence in synthesizing and analyzing the development as anti-cancer agonists.

Communicated by Ramaswamy H. Sarma

Keywords:

• PPAR-γ
• cancer
• molecular docking
• and molecular dynamic simulation

Acknowledgements

The authors are thankful to Dr. D. Y. Patil Biotechnology and Bioinformatics Institute, Dr. D. Y. Patil Vidyapeeth, Pune for the physical infrastructure and Department of Science and Technology Science and Engineering Research Board (DST-SERB), Govt. of India, New Delhi, (File Number: ECR/2016/000943) for financial support and S. Ballav is thankful to DST-SERB for Junior Research Fellowship.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Authors also acknowledge the support of DST-SERB, Govt. of India, New Delhi, for utilizing an optimized supercomputer for docking and dynamics calculations (File Number: YSS/2015/002035). Senior Research Fellowship awarded to K. B. Lokhande (Project ID: 2019-3458; File No.: ISRM/11(54)/2019) of the Indian Council of Medical Research, New Delhi is also acknowledged.