High-Throughput Structure-Based Drug Design of Chalcones Scaffolds as Dual Inhibitor of Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1

Cyclooxygenase-2 (COX-2) inhibitors had been extensively used to treat inflammatory disorders. However, the increased incidence of cardiovascular side effects had limited the usage of the drugs. The emergence of microsomal prostaglandin E synthase-1 (mPGES-1) as newly recognized therapeutic target for inflammation and pain gave new hope to develop anti-inflammatory drug with minimal adverse effects. Thus, selective inhibition of COX-2 and mPGES-1 is expected to provide anti-inflammatory effects without the side effects. Chalcone is a compound derived from nature with various pharmacological activities. Based on its favorable activity, chalcone framework had been used to identify novel derivatives for anti-inflammatory properties. Hence, the present study aims to identify chalcone derivatives that can reduce the production of the inducible PGE2 by targeting COX-2 and mPGES-1 using structure-based drug design. A hybrid pharmacophore model of COX-2 named as “phore 1” was developed and used to screen chalcone derivatives from ASINEX database. Forty-two compounds were successfully mapped on “phore 1” and only 15 compounds were selected based on docking. These compounds were then subjected to pharmacophore screening and followed by docking for mPGES-1. Three lead compounds (BAS00384673, BAS00643043 and BAS02557914) were found to be selective towards COX-2 and have good binding interaction with mPGES-1.