Cyclooxygenase (COX) is a key enzyme in the biosynthetic pathway leading to the formation of prostaglandins, which are mediators of inflammation. It exists mainly in two isoforms COX-1 and COX-2. The conventional nonsteroidal anti-inflammatory drugs (NSAIDs) have gastrointestinal side effects because they inhibit both isoforms. Recent data demonstrate that the overexpression of these enzymes, and in particular of cyclooxygenases-2, promotes multiple events involved in tumorigenesis; in addition, numerous studies show that the inhibition of cyclooxygenases-2 can delay or prevent certain forms of cancer. Agents that inhibit COX-2 while sparing COX-1 represent a new attractive therapeutic development and offer a new perspective for a further use of COX-2 inhibitors. The present study extends the evaluation of the COX activity to all 203 possible natural tripeptide sequences following a rational approach consisting in molecular modeling, synthesis, and biological tests. Based on data obtained from virtual screening, only those peptides with better profile of affinity have been selected and classified into two groups called S and E. Our results suggest that these novel compounds may have potential as structural templates for the design and subsequent development of the new selective COX-2 inhibitors drugs. 1. Introduction The main cause of the inflammation is the prostaglandins overproduction, which are synthesized by cyclooxygenase enzymes [1]. Prostaglandin-endoperoxide synthase, commonly called cyclooxygenase (COX), is an intracellular enzyme required for the conversion of arachidonic acid to prostaglandins. The two best-known COX isoforms are referred to as COX-1 and COX-2 for the order in which they were discovered [2]. The first isozyme is constitutively expressed in resting cells of most tissues, functions as a housekeeping enzyme, and is responsible for maintaining homeostasis (gastric and renal integrity) and normal production of prostaglandins; vice versa, the COX-2 expression is induced by infection and it is responsible for the inflammatory response. Such a difference suggested to report COX-1 as the constitutive form and COX-2 as the inducible one. More recently, the constitutive presence of COX-2 has been highlighted in brain, kidney, and endothelial cells but is virtually absent in most other tissues. In particular, COX-2 expression is significantly upregulated as part of various acute and chronic inflammatory conditions and in neoplastic tissues. The design of a selective inhibitor is difficult as the COX-1 and COX-2 binding sites are almost
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