Pancreatic lipase inhibition by papaverine: investigation by simulated molecular docking and subsequent in vitro evaluation

In order to develop safe and effective lipid lowering drug that affecting the absorption of dietary lipids. the pancreatic lipase inhibitory effect of papaverine alkaloid was probed. The investigation included molecular docking to fit papaverine into the binding site of pancreatic lipase employing optimal set of parameters succeeded in retrieving the closest model to the cocrystallized pose. Docking simulation suggested four binding modes for papaverine. The highest ranking binding mode have potential hydrophobic interactions with the key aniino acids Phe-215, Ala-178, Pro-180 and Ala-259 and potential aromatic stacking between isoquinoline ring and Phe-77 and Tyr-114. Moreover, papaverine forms strong hydrogen bonds with the key amino acid Ser-152 in the catalytic triad. Experimentally, papaverine illustrated substantial in vitro inhibitory effect against PL with IC[50] = 36.2 microg/ml [106.6 microM]

comparative enzymatic inhibition assay as a surrogate indicator of pharmaceutical and potency equivalence of two orlistat formulations

The most practical measure of therapeutic equivalence between two commercially available and generic formulation of a certain drug is to determine their in vivo bioavailability. However, for the oral dosage form that is not intended to be absorbed [e.g. orlistat], in vivo bioavailability studies are irrelevant to the achievement of the product's intended purposes. However, specific requirements for these drug products may be set in a way that they should meet acceptable in vitro standards. For this purpose, a comparative enzymatic inhibition assay of the target enzyme, pancreatic lipase, was developed to demonstrate orlistat products' pharmaceutical and potency equivalence. In this study we compared the pancreatic lipase inhibition that is achieved by two orlistat formulations; a generic product manufactured by local company [Jordan Sweden Medical Company, JOSWE] and the reference one Xenical manufactured by Roche. The inhibition was expressed by the concentration of product which inhibits 50% of the activity of the pancreatic lipase enzyme [IC[50]]. The results of these studies showed that both formulations have equivalent potency that was demonstrated by in vitro studies