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

Sanjay, Kottekad and Sudip, Roy and Usharani, D. (2022) A computational study to probe the binding aspects of potent polyphenolic inhibitors of pancreatic lipase. Journal of Biomolecular Structure and Dynamics.

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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 (DGMMGBSA) assured the binding poses are more true positives. Further, understanding of each class and subclasses of polyphenols indicated tannins preferred non-catalytic site wherein bind�ing 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 mM for better in vivo efficacy. The prediction of bioactivity, drug-like�ness 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.

Item Type:	Article
Uncontrolled Keywords:	Pancreatic lipase; polyphenols; flavonoids; molecular simulations; well-tempered metadynamics; obesity
Subjects:	500 Natural Sciences and Mathematics > 04 Chemistry and Allied Sciences > 18 Flavonoid Chemistry
Divisions:	Food Safety Analytical Quality Control Lab
Depositing User:	Food Sci. & Technol. Information Services
Date Deposited:	24 May 2023 05:00
Last Modified:	24 May 2023 05:00
URI:	http://ir.cftri.res.in/id/eprint/16447

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