Discovery and Mechanism of Action of Small Molecule Inhibitors of Ceramidases**

Abstract

Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes in human physiology. The central metabolite is ceramide,apro-apoptotic lipid catabolized by ceramidase enzymes to produce pro-proliferative sphingosine-1-phosphate.Alkaline ceramidases are transmembrane enzymes that recently attracted attention for drug development in fatty liver diseases.H owever,d ue to their hydrophobic nature,nospecific small molecule inhibitors have been reported. We present the discovery and mechanism of action of the first drug-like inhibitors of alkaline ceramidase 3 (ACER3). In particular,w ec hemically engineered novel fluorescent ceramide substrates enabling screening of large compound libraries and characterized enzyme:inhibitor interactions using mass spectrometry and MD simulations.I n addition to revealing an ew paradigm for inhibition of lipid metabolising enzymes with non-lipidic small molecules,o ur data lay the ground for targeting ACER3 in drug discovery efforts.

Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study

“…The geometry of the protein was optimized by applying the MMFF94x force field and conf search module in the default mode in the MOE program. Next, the docking protocol was examined for validation by docking the original co-crystallized ligand/inhibitor to the binding pocket of the targeted protein by utilizing the London dG scoring function and Triangle Matcher placement method [ 102 , 103 , 104 , 105 , 106 , 107 , 108 ]. The validated protocol was then used to explore the binding affinity of carvedilol toward the active sites of the DNM1L and MID51 proteins.…”

The Binary Mixtures of Lambda-Cyhalothrin, Chlorfenapyr, and Abamectin, against the House Fly Larvae, Musca domestica L.

“…Computational techniques have shown the power to assess the binding affinity of a certain compound toward the active site of a targeted protein [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. The affinity of insecticides, chlorfenapyr, abamectin, and lambda-cyhalothrin, was evaluated toward the active sites of cytochrome P450 and glutathione S-transferase proteins.…”

“…In our study, we have used the following crystal structures for the targeted proteins; PDB code; 6a18 for cytochrome P450 90B1 protein, and 2imk for glutathione S-transferase [ 35 , 36 ]. The 3D X-ray crystal structures of the targeted proteins were downloaded from PDB website ( (10 March 2022)) and were adjusted as previously reported [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 43 ]. ChemDraw professional was used to obtain the 2D structures of chlorfenapyr, abamectin, and lambda-cyhalothrin.…”

Secondary Metabolites of Actinomycetales as Potent Quorum Sensing Inhibitors Targeting Gram-Positive Pathogens: In Vitro and In Silico Study

“…The molecular docking simulation study was performed using Molecular Operating Environment (MOE ® ) 2008.10 software [ 58 , 59 , 60 , 61 , 62 , 63 ]. The crystal structure of Staphylococcus aureus AgrA (PDB code: 3BS1) was retrieved from Protein Data Bank [ 49 ].…”

“…The structure of AgrA was prepared for molecular docking using the Protonate 3D protocol in MOE with the default options. The Triangle Matcher placement method and London dG scoring function were applied in the docking protocol according to the reported procedure [ 58 , 59 , 60 , 64 , 65 , 66 , 67 ].…”