Structure and Ligand Based Drug Design Strategies in the Development of Novel 5- LOX Inhibitors

Abstract

Lipoxygenases (LOXs) are non-heme iron containing dioxygenases involved in the oxygenation of polyunsaturated fatty acids (PUFAs) such as arachidonic acid (AA). Depending on the position of insertion of oxygen, LOXs are classified into 5-, 8-, 9-, 12- and 15-LOX. Among these, 5-LOX is the most predominant isoform associated with the formation of 5-hydroperoxyeicosatetraenoic acid (5-HpETE), the precursor of non-peptido (LTB4) and peptido (LTC4, LTD4, and LTE4) leukotrienes. LTs are involved in inflammatory and allergic diseases like asthma, ulcerative colitis, rhinitis and also in cancer. Consequently 5-LOX has become target for the development of therapeutic molecules for treatment of various inflammatory disorders. Zileuton is one such inhibitor of 5-LOX approved for the treatment of asthma.In the recent times, computer aided drug design (CADD) strategies have been applied successfully in drug development processes. A comprehensive review on structure based drug design strategies in the development of novel 5-LOX inhibitors is presented in this article. Since the crystal structure of 5-LOX has been recently solved, efforts to develop 5-LOX inhibitors have mostly relied on ligand based rational approaches. The present review provides a comprehensive survey on these strategies in the development of 5-LOX inhibitors.

Investigating the Selectivity of Metalloenzyme Inhibitors

“…65 5-LOX functions endogenously to convert cis -polyunsaturated fatty acids into leukotrienes, first adding molecular oxygen to the fifth carbon on the fatty acid, generating a hydroperoxide, and subsequently dehydrating the hydroperoxide to yield an epoxide-containing leukotriene. 66 The leukotrienes trigger an inflammatory response leading to bronchoconstriction.…”

MK886 Reduces Cerebral Amyloid Angiopathy Severity in TgCRND8 Mice

“…Leukotrienes are inflammatory mediators that are implicated in asthma, ulcerative colitis and cancer [8]. Recently, leukotriene B 4 has been identified as a physiological agonist of peroxisome proliferator-activated receptor-α (PPARα), a member of the nuclear hormone receptor family that regulates the transcription of genes involved in inflammation and lipid metabolism, including apolipoprotein (apo) A-I, apoE and low density lipoprotein receptor-related protein-1 (LRP-1) [9,10].…”

Discovery of novel inhibitors of human S-adenosylmethionine decarboxylase based on in silico high-throughput screening and a non-radioactive enzymatic assay

“…Putrescine was reported to be able to stimulate the activity of hAdoMetDC52223242541, so we tested the role of putrescine with this assay. Firstly, according to the reported data, we tested different concentrations of putrescine to evaluate the possible background effect.…”

“…Therefore, the recent years have witnessed the increasing use of time- and cost-saving computer aided drug design (CADD) in lead identification and optimization22232425. One widely adopted strategy in CADD is in silico high-throughput (HTP) drug screening based on protein 3D structures, which, to be really fruitful, is generally followed up by complementary experimental HTP screening procedures262728.…”