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

Author(s): Polamarasetty Aparoy, Kakularam Kumar Reddy, Pallu Reddanna.

Journal Name: Current Medicinal Chemistry

Volume 19 , Issue 22 , 2012

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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.

Keywords: Arachidonic acid, 5-LOX, asthma, drug design, pharmacophore, QSAR, scaffold hopping, pseudoreceptor

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Article Details

VOLUME: 19
ISSUE: 22
Year: 2012
Page: [3763 - 3778]
Pages: 16
DOI: 10.2174/092986712801661112

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