Virtual Screening, Molecular Docking, and Physiochemical Analysis of Novel 1,3-diphenyl-2-propene-1-one as Dual COX-2/5-LOX Inhibitors

Abstract

Background: Chronic inflammation is usually combated with non-steroidal anti-inflammatory drugs (NSAIDs). However, long-term use of NSAIDs causes side effects comprising gastric ulceration, abdominal discomfort, lack of anti-thrombolytic activity, and myocardial infarction. Emerging reports indicate alteration of arachidonic acid metabolism, via cyclooxygenase and lipoxygenase pathways, being investigated as potential anti-inflammatory agents. There is a dynamic balance shift toward lipoxygenase on cyclooxygenase inhibition, therefore there is a need to identify naïve dual COX-2/5-LOX inhibitory agents with better therapeutic and minimal side effects. Objective: The current research focused on identifying a prospective natural candidate molecule (1,3- diphenyl-2-propene-1-one derivative) as a dual COX-2/5-LOX inhibitor by using structure-based database screening, molecular modelling, and in-silico ADMET analysis. Methods: Virtual screening using the ZINC database, molecular docking of potential compounds, and ADME analysis of hit compounds were performed. Results: A virtual library of 116 chalcone-based molecules was screened out. The molecules were docked for COX-2 (PDB ID-3LN1) and 5-LOX (PDB ID-3V99) enzymatic active pockets and resulted in compounds C96, C8, C83, C45, C20 better than zileuton. The potent compounds and zileuton showed good binding affinity in the range of -8.0 to -8.7Kcal/mol in the COX-2 and -7.0 to -8.7Kcal/mol in the 5- LOX active site respectively. These compounds were further subjected to ADME analysis giving two plausible lead compounds C45 and C64 following ideal pharmacokinetic properties. Conclusion: The research work provides abundant opportunities to explore computational and medicinal research areas which will facilitate the development of novel dual COX-2/5-LOX inhibitors in future experimental studies.