Application of Docking Analysis in the Prediction and Biological Evaluation of the Lipoxygenase Inhibitory Action of Thiazolyl Derivatives of Mycophenolic Acid

Abstract

5-LOX inhibition is among the desired characteristics of anti-inflammatory drugs, while 15-LOX has also been considered as a drug target. Similarity in inhibition behavior between soybean LOX-1 and human 5-LOX has been observed and soybean LOX (sLOX) type 1b has been used for the evaluation of LOX inhibition in drug screening for years. After prediction of LOX inhibition by PASS and docking as well as toxicity by PROTOX and ToxPredict sixteen (E)-N-(thiazol-2-yl)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydroisobenzofuran-5-yl)-4-methylhex-4-enamide derivatives with lengths varying from about 15–20 Å were evaluated in vitro for LOX inhibitory action using the soybean lipoxygenase sLOX 1b. Docking analysis was performed using soybean LOX L-1 (1YGE), soybean LOX-3 (1JNQ), human 5-LOX (3O8Y and 3V99) and mammalian 15-LOX (1LOX) structures. Different dimensions of target center and docking boxes and a cavity prediction algorithm were used. The compounds exhibited inhibitory action between 2.5 μΜ and 165 μΜ. Substituents with an electronegative atom at two-bond proximity to position 4 of the thiazole led to enhanced activity. Docking results indicated that the LOX structures 1JNQ, 3V99 and 1LOX can effectively be used for estimation of LOX inhibition and amino acid interactions of these compounds.

Long-Lasting Anti-Inflammatory and Antinociceptive Effects of Acute Ammonium Glycyrrhizinate Administration: Pharmacological, Biochemical, and Docking Studies

“…The human 5-LO structure (PDB ID: 3V99) [32] in complex with its substrate, arachidonic acid (AA), was used as the target for molecular docking studies [33]. The computational analysis highlighted two possible binding modes for the AG molecule (Figure 12), compatible with two different class of direct 5-LO inhibitors [30].…”

“…Several investigators have reported that the anti-inflammatory mechanism of AG involves cytokines such as IFN-γ, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, and IL-17 [37,38,39,40,41,42], intercellular cell adhesion molecule 1 (ICAM-1) and P-selectin, enzymes such as iNOS, and transcription factors such as NF-kappaB, signal transducer and activator of transcription (STAT)-3 and STAT-6 [33].…”

Thymus algeriensis and Thymus fontanesii: Chemical Composition, In Vivo Antiinflammatory, Pain Killing and Antipyretic Activities: A Comprehensive Comparison

“…The catalytic center of 5-LOX mainly consists of hydrophobic amino acids, such as Ile406, Ala410, Leu414, Ile425, Val604 and Leu607. The carboxylic group of arachidonic acid seems to interact with Phe177 of 5-LOX, in addition to the hydrophobic contacts [35].…”

Lipoxygenase Inhibition Activity of Coumarin Derivatives—QSAR and Molecular Docking Study

“…Thiazolyl derivatives of mycophenolic acid were placed at the active site of the soybean LOX-3, interacting with the amino acids HIS518, LEU773, GLN716, and ASN713. The compound with the highest binding affinity formed hydrogen bonds with HIS518, ASN713, and GLN716 [ 48 ]. Similarly, as in the present study, the best docking scores for soybean LOX-3 (PDB ID: 1JNQ) and 5-LOX (PDB ID: 3V99) were obtained for the same compound that showed the best soybean lipoxygenase inhibition.…”