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QSAR and Docking Studies on Propenone Derivatives as Dual COX and 5- LOX Inhibitors

30 Sep 2008-Letters in Organic Chemistry-Vol. 5, Iss: 7, pp 544-554

AboutThis article is published in Letters in Organic Chemistry.The article was published on 2008-09-30. It has received 2 citation(s) till now. The article focuses on the topic(s): Docking (molecular). more

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TL;DR: A comprehensive review on structure based drug design strategies in the development of novel 5-LOX inhibitors is presented in this article.
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.

100 citations

Cites background from "QSAR and Docking Studies on Propeno..."

  • ...Further Mukesh Doble and his group developed QSAR model of seventeen propenone derivatives [117], which were reported to be COX-2/5LOX dual inhibitors [98]....


Journal ArticleDOI
Abstract: Invasion and metastasis are responsible for 90% of cancer-related mortality. Herein, we report on our quest for novel, clinically relevant inhibitors of local invasion, based on a broad screen of natural products in a phenotypic assay. Starting from micromolar chalcone hits, a predictive QSAR model for diaryl propenones was developed, and synthetic analogues with a 100-fold increase in potency were obtained. Two nanomolar hits underwent efficacy validation and eADMET profiling; one compound was shown to increase the survival time in an artificial metastasis model in nude mice. Although the molecular mechanism(s) by which these substances mediate efficacy remain(s) unrevealed, we were able to eliminate the major targets commonly associated with antineoplastic chalcones.

11 citations