Towards a systematic analysis of structure-activity relationships of 5-LOX inhibitors through activity landscape and chemotype enrichment

Pharmacological inhibition of the 5-lipoxygenase (5-LOX) pathway used to inhibit leukotrienes’ production (LT) has been shown to have therapeutic properties in many respiratory and allergic diseases. Because of the toxicity effect of FDA approved orally active 5-LOX inhibitor, zileuton, the scientific community is seeking novel 5-LOX inhibitors. As a result, the significant and relevant amount of structure-activity information of 5-LOX inhibitors and its activating protein inhibitors, i.e., FLAP inhibitors, has been released and stored in public databases. To the best of our knowledge, there are no detailed analyzes of their structure-activity relationship (SAR) so far. This study has tried to locate, characterize, and extract SAR from the ChEMBL database and present them intuitively using activity landscape analysis and chemotype enrichment study. We have found eight important activity cliff generators and more than six cyclic systems with a large proportion of active molecules for each protein. These molecules can provide key information on the pharmacophoric regions that are significant to determine their potency. Therefore, they can be used for lead optimization. Besides, this study found that the smooth SAR region in the 5-LOX chemical space’s activity landscape opens up the possibility of developing robust and reliable QSAR models. •Systematic characterization of SAR of the 5-LOX and FLAP inhibitors.•Activity landscape analysis shows an overall heterogeneous SAR.•Identified eight important active cliff generators.•Conducted Chemotype Enrichment analysis.•Identified cyclic systems with a large proportion of active molecules.