Discovery of selective COX-2 inhibitors resulted in anti-inflammatory drugs with significantly reduced gastrointestinal adverse effects. Thus, the need for newer and safer selective COX-2 inhibitors still exists due to their anti-inflammatory properties and other potential therapeutic uses in the treatment of cancer, Alzheimer's, dementia, and glaucoma. Research efforts in the discovery of newer drugs have proven to be very expensive in terms of resources as well as time. Virtual screening is a successful method to identify novel ligands from large chemical databases. Shape signatures are a highly effective virtual screening tool to discover novel selective COX-2 inhibitors. In-vitro experiments have confirmed the usefulness of shape signatures in the identification of several compounds, which are effective COX-2 inhibitors and have never been tested before for this purpose. The present finding encourages a more general use of this effective virtual screening tool for the identification of potential leads for medically important disease targets.