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

• Published in: Journal of biomolecular structure & dynamics 2024-05, Vol.42 (7), p.3472-3491
• Main Authors: Kottekad, Sanjay, Roy, Sudip, Dandamudi, Usharani
• Format: Article
• Language: English
• Subjects: flavonoids; molecular simulations; obesity; Pancreatic lipase; polyphenols; well-tempered metadynamics
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2023.2212795

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 IC 50 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 pIC 50 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 IC 50 < 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.