A cheminformatic study on chemical space characterization and diversity analysis of 5-LOX inhibitors

Abstract

The process of blocking 5-lipoxygenase (5-LOX) catalyzed leukotriene biosynthesis has been recognized for the past few decades as a promising therapeutic strategy for acute inflammatory, allergic, and respiratory diseases. Due to the toxicity effect of FDA approved 5-LOX inhibitor zileuton, novel 5-LOX inhibitors have been sought by the scientific community. As a result, a significant and relevant amount of information on the structure-activity of 5-LOX inhibitors has been released and stored in public databases. In this study, we aimed at the comprehensive cheminformatic characterization of the diversity and complexity of the chemical space of 5-LOX inhibitors and its activating protein FLAP inhibitors by comparing it with the Approved drug space and virtual LOX library. The visual representation of the property space indicates some compounds in the 5-LOX inhibitors space broaden the traditional medicinal space. The structural diversity of the databases is computed using complementary approaches, including Physicochemical Property (PCP) descriptors, molecular fingerprints, and molecular scaffold. With the apparent exception of approved drugs, the 5-LOX dataset shows more diversity compared to FLAP and LOX virtual library set. This study was able to identify the underlying patterns in the chemical and pharmacological properties space that were decisive for the drug discovery and development of 5-LOX inhibitors.