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

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.