The inhibitors of 5-LOX control the overproduction of pro-inflammatory mediatorsknownas leukotrienes

(LTs) and thus have therapeutic relevance in the treatment of various diseases like asthma, rheumatoid

arthritis, inflammatory bowel disease and certain types of cancers. This has increased the search for efficient

therapeutic agents for protein 5-LOX and this process is now primarily based on QSAR. In this study,

wehave developed four different quantitative structure and 5-LOX inhibition activity relationship models

of benzoquinone derivative by exploiting CoMFA, RF, SVM, and MLR chemometric methods. Performance

of the QSAR models was measured by using cross-validation technique as well as through the external

test set prediction. RF model outperforms all other models. SVM and MLR models failed due to the poor

performance of the external test set prediction. CoMFA model, which shows relatively good performance

was used to explore the essential structural regions where the modification was necessary to design a

novel scaffold with improved activity. Moreover, molecular docking of all the derivatives to the binding

site of 5-LOX was done to show their binding mode and to identify critical interacting residues inside the

active site of 5-LOX. The docking result confirms the stability and rationality of the CoMFA model.