How Does Catalase Release Nitric Oxide? A Computational Structure–Activity Relationship Study

Abstract

Hydroxyurea (HU) is the only FDA approved medication for treating sickle cell disease in adults. The primary mechanism of action is pharmacological elevation of nitric oxide (NO) levels which induces propagation of fetal hemoglobin. HU is known to undergo redox reactions with heme based enzymes like hemoglobin and catalase to produce NO. However, specific details about the HU based NO release remain unknown. Experimental studies indicate that interaction of HU with human catalase compound I produces NO. Presently, we combine flexible receptor-flexible substrate induced fit docking (IFD) with energy decomposition analyses to examine the atomic level details of a possible key step in the clinical conversion of HU to NO. Substrate binding modes of nine HU analogs with catalase compound I were investigated to determine the essential properties necessary for effective NO release. Three major binding orientations were found that provide insight into the possible reaction mechanisms for producing NO. Further results show that anion/radical intermediates produced as part of these mechanisms would be stabilized by hydrogen bonding interactions from distal residues His75, Asn148, Gln168, and oxoferryl-heme. These details will ideally contribute to both a clearer mechanistic picture and provide insights for future structure based drug design efforts.

Identification of Potential Insect Growth Inhibitor against Aedes aegypti: A Bioinformatics Approach

“…It can be found in the Scientific Opinion of the Panel on Plant Protection Products and Their Residues (PPR Panel), at the request of the PRASA Unit of the European Food Safety Authority (EFSA), on the genotoxic and carcinogenic potential of buprofezin in the context of human risk assessment. It was evaluated in a two-year study that, in mice and rats, neither the nature nor the incidence of tumors was affected by its administration [ 116 ]. However, with teflubenzuron, the main target organ of which is the liver, after short or long-term exposure in species of rats, mice, or dogs, hepatotoxicity was observed in an 18-month oncogenicity study in mice.…”

“…After the high-performance pharmacophoric screening of the studied compounds, only M01 presented urea in its molecular structure. M01 and its derivatives have 19 studies and patents that are mainly related to antibacterial tests, nitric oxide, DNA inhibition, neuroinflammatory treatment and autoimmune diseases, ribonucleotide reductase, tyrosinase inhibitors, and sickle cell anemia treatments [ 116 , 117 , 129 , 130 , 131 , 132 , 133 , 134 ].…”

Elucidating a chemical defense mechanism of Antarctic sponges: A computational study

“…Previous work by Weihua Li et al has shown that refining homology models via MD simulation can be a necessary step in accurately predicting ligand binding modes in P450 proteins (e.g., CYP2J2). 46 From our own past experience with flexible docking studies, 47,48,49,50,51 we have also seen that it is advisable to utilize protein structures with receptor conformations that are predisposed to ligand binding (i.e.,"productive" conformations). Past research has shown that apo P450 binding sites in particular can be very malleable, 52,53 therefore "holo-like" structures were desirable, i.e., protein structures similar to those with a bound ligand, to ensure we had productive receptor conformations for docking.…”

“…The choice of a 9Å mutated region is not a default condition, but our group has seen that specifying a larger region here allows for more accurate binding mode predictions, especially when docking larger ligands. 47,48 To initiate docking, Glide (Grid-base ligand docking with energetics) receptor grids were generated with CPS identified as the centroid of the protein active site. 57,58 Schrödinger's LigPrep 2.3 module was used to pre-process substrate structures at pH 8 (not default) 3 to generate relevant protonation states, tautomers, and energy minimized molecular structures.…”

ProBiS-CHARMMing: Web Interface for Prediction and Optimization of Ligands in Protein Binding Sites

“…Apoprotein binding sites often differ from their holo counterparts, because of induced fit effects upon ligand binding, which alters the spatial arrangement of the binding site’s residues. It has been shown that molecular docking to an holoprotein’s binding site results in higher enrichment, i.e., ability to discriminate between active and inactive compounds, compared to when docking is performed to apo structures. , The binding site cavity in an apoprotein can often be too small to accommodate drug-sized molecules, which prevents docking altogether. , When only the apoprotein is available in the PDB, it would thus be of great benefit to docking if we could make the binding site more similar to a holoprotein. One method to accomplish this is to predict the binding pose of a ligand from another similar crystal structure, dock it to the binding site of the apoprotein, and then minimize the geometries of both the ligand and the protein to make it resemble the interactions in the holo form.…”