Ellagic acid: A potent glyoxalase-I inhibitor with a unique scaffold

Abstract

The glyoxalase system, particularly glyoxalase-I (GLO-I), has been approved as a potential target for cancer treatment. In this study, a set of structurally diverse polyphenolic natural compounds were investigated as potential GLO-I inhibitors. Ellagic acid was found, computationally and experimentally, to be the most potent GLO-I inhibitor among the tested compounds which showed an IC50 of 0.71 mmol L−1. Its binding to the GLO-I active site seemed to be mainly driven by ionic interaction via its ionized hydroxyl groups with the central Zn ion and Lys156, along with other numerous hydrogen bonding and hydrophobic interactions. Due to its unique and rigid skeleton, it can be utilized to search for other novel and potent GLO-I inhibitors via computational approaches such as pharmacophore modeling and similarity search methods. Moreover, an inspection of the docked poses of the tested compounds showed that chlorogenic acid and dihydrocaffeic acid could be considered as lead compounds worthy of further optimization.

In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

“…The crystal complexes of the selected targets were prepared, solvated, and minimised as detailed in the methods section. These preparations were performed in order to relax the complex and remove any possible distortions resulting from crystal packing 74 , 75 . Then, the binding site in each of the selected crystal structures was defined.…”

“…Then, the prepared crystal structures were solvated by immersing them in a box of pre-equilibrated TIP3 water molecules using the Solvation protocol. After solvation, they were sequentially minimised in three stages using the Minimisation protocol with default parameters as detailed previously [74][75][76] . Finally, all water molecules and counterions were deleted, then the binding sites were defined based on the cocrystallized ligands using the Define and Edit Binding Site tool, and then the ligands were deleted.…”

Natural products can be used in therapeutic management of COVID-19: Probable mechanistic insights

“…Ellagic acid with a molecular weight of 302.197 g mol −1 and a melting point of 350 °C is a highly thermostable molecule [166] . The structural feature of ellagic acid represents four lipophilic domains that form hydrogen-bond sides, four phenolic groups that function as electron acceptors, and two lactones that denote the hydrophilic domain [167] , [168] . Ellagic acid is found in the forms of hydrolyzable tannins called ellagitannins in many fruits, in particular raspberries, strawberries, pomegranate, persimmon, grapes, black currants, plums, mango, guava, walnuts, almonds, longan seeds and green tea [82] , [83] , [84] .…”

Tackling COVID-19: identification of potential main protease inhibitors via structural analysis, virtual screening, molecular docking and MM-PBSA calculations

“…Then it was minimized in three stages using the Minimization protocol within DS. In the first stage, the backbone and sidechain heavy atoms were harmonically restrained; in the second stage, only backbone heavy atoms were restrained; and in the final stage, no restraints were applied and the entire system was allowed to flex (Al-Shar'i et al, 2019, 2021. The minimization was conducted using the smart minimizer algorithm, where the first 1000 steps of minimization were performed using the steepest descent algorithm (Meza, 2010) and then completed to 5000 steps using the conjugate gradient algorithm (Fletcher & Reeves, 1964).…”