Molecular dynamics simulations to decipher the hotspots at the allosteric site of human 5-lipoxygenase.

Human 5-lipoxygenase (LOX) is a non-heme, Fe-containing LOX which catalyses the conversion of arachidonic acid (AA) to leukotriene A4 (LTA4). LTA4 is subsequently converted to cysteinyl-LTs and LTB4 that cause bronchoconstriction and act as chemotactic and chemokinetic agent on human leukocytes, respectively. Leukotrienes play significant roles in inflammation in asthma, cardiovascular diseases, allergic rhinitis, atopic dermatitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis and many more. Thus, in order to suppress LT formation for the management of such diseases, the intrinsic details of the structure of 5-LOX are crucial for the design/development of 5-LOX inhibitors. Here, we deciphered the role of various amino acids at the allosteric site of 5-LOX through molecular dynamics simulations. 3-O-Acetyl-11-keto-beta-boswellic acid (AKBA), a well-recognized allosteric inhibitor of 5-LOX, was used as reference compound. The consequences of amino acid mutations (R101, E108, H130, E134) on AKBA binding have been studied in silico. The changes were characterized at the interaction level. Our observations provide structural insights into crucial residues which are important for stabilizing the ligand at the allosteric site. Principal component analysis (PCA) was applied to the molecular dynamics simulation data to identify the structural fluctuations in the 5-LOX structure. The derived mechanistic details of allosteric 5-LOX inhibition may facilitate the development of novel therapeutics targeting 5-LOX.