Cyclooxygenase-2 (COX-2) is an inducible inflammatory enzyme, which produces prostanoids from arachidonic acid. COX-2 overexpression and over-activity can cause inflammation, tumorigenesis, and angiogenesis. Prostanoids are the main reason for the inflammation, and increase of mitogenesis by COX-2. So, any change such as mutations that can lead to COX-2 over-activity could ignite the tumor situations with increase of prostanoids production is one of its ways. The aim of this study was to check the effect of 166 missense mutations of COX-2 on protein features that can affect the COX-2 activity such as protein stability, fluctuation, 2D structure, and its binding affinity with the substrate by in silico methods, network modeling, and docking calculations, by which 44 of them shown to be deleterious. Among them, the S124I and S474F mutations can increase the stability of the protein. 11.36% of deleterious nsSNPs were part of the substrate-binding region among which the M508T, H337R, and V511G have the potential to affect the protein by 2D structure alteration. V511G can improve binding affinity and H337R showed a small decrease in the deformation overall energy that can represent a decrease in the stability of COX-2. Also, L517S showed a significant decrease in the binding power of COX-2/substrate but based on the anisotropic network modeling this mutation has a dual effect on COX-2 stability. These nsSNPs/mutations have the potential causing an increase or decrease of tumorigenesis because increasing of COX-2 stability and its binding affinity can lead to altering its activity.
