In search of novel anti-inflammatory agents: Computational repositioning of approved drugs

• The present study describes an application of computational drug repositioning for anti-inflammatory indication. Using a set of three query molecules (diclofenac, celecoxib and a potent mPGES-1 inhibitor) acting on different targets in the PG biosynthetic pathway, shape- and electrostatics-based virtual screening was performed on a database of approved small molecule drugs.
• Detailed literature search of the top 100 hits from each of the lists led to interesting reports wherein the hits were found to exhibit anti-inflammatory activity. This validated the repurposing hypothesis generated using the computational analyses.
• Experimental evaluations of few of these hits in target-specific or phenotypic assays may yield useful starting points either for drug repositioning or drug discovery.
• Such interesting investigations and the finding therein may advance our knowledge of the therapeutic area, in general.

Computational drug repositioning is a powerful tool to guide the experimental drug repositioning campaigns. Both structure-based (e.g., reverse docking) and ligand-based (e.g., 3D pharmacophore) approaches can be used for the generation of repurposing hypotheses. In an attempt to discover novel anti-inflammatory agents, computational repurposing of approved small molecule drugs was undertaken using diclofenac (nonselective cyclooxygenase (COX) inhibitor), celecoxib (selective COX-2 inhibitor) and a potent microsomal prostaglandin E synthase – 1 (mPGES-1) inhibitor as query molecules for shape- and electrostatics-based virtual screening. Several approved drugs (other than anti-inflammatory) were amongst the top 5% of the hits. These hits (approved drugs) may serve as starting points for clinical repositioning (anti-inflammatory indication) or as lead structures in drug discovery programs.