A computational study to probe the binding aspects of potent polyphenolic inhibitors of pancreatic lipase

Abstract

Pancreatic lipase (PL) is a keen target for anti-obesity therapy that reduces dietary fat absorption. Here, we investigated the binding patterns of 220 PL inhibitors having experimental IC₅₀ values, using molecular docking and binding energy calculations. Screening of these compounds illustrated most of them bound at the catalytic site (S1-S2 channel) and a few compounds are at the non-catalytic site (S2-S3 channel/S1-S3 channel) of PL. This binding pattern could be due to structural uniqueness or bias in conformational search. A strong correlation of pIC₅₀ values with SP/XP docking scores, binding energies (ΔG_MMGBSA) assured the binding poses are more true positives. Further, understanding of each class and subclasses of polyphenols indicated tannins preferred non-catalytic site wherein binding energies are underestimated due to huge desolvation energy. In contrast, most of the flavonoids and furan-flavonoids have good binding energies due to strong interactions with catalytic residues. While scoring functions limited the understanding of sub-classes of flavonoids. Hence, focused on 55 potent PL inhibitors of IC₅₀ < 5 µM for better in vivo efficacy. The prediction of bioactivity, drug-likeness properties, led to 14 bioactive compounds. The low root mean square deviation (0.1-0.2 nm) of these potent flavonoids and non-flavonoid/non-polyphenols PL-inhibitor complexes during 100 ns molecular dynamics runs (MD) as well as binding energies obtained from both MD and well-tempered metadynamics, support strong binding to catalytic site. Based on the bioactivity, ADMET properties, and binding affinity data of MD and wt-metaD of potent PL-inhibitors suggests Epiafzelechin 3-O-gallate, Sanggenon C, and Sanggenofuran A shall be promising inhibitors at in vivo conditions.

Communicated by Ramaswamy H. Sarma

Binding aspects of natural compounds reveal the crucial factors of bioactivity towards pancreatic lipase.

Keywords:

• Pancreatic lipase
• polyphenols
• flavonoids
• molecular simulations
• well-tempered metadynamics
• obesity

Acknowledgments

SK and UD thank CSIR-CFTRI, Mysore for computing facilities. SK thanks DBT, India (GAP0462) and CSIR, New Delhi for the junior research fellowship. UD thank in house CSIR project (MLP -212). We thank Mrs. Megha J and Mrs. Amrutha Joshi for the initial collection of PL inhibitors. Dr. Sudarshan of Schrodinger for his inputs.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by Department of Biotechnology, Ministry of Science and Technology, India.