Prostanoids, namely prostaglandins, prostacyclin, and thromboxanes, are potent lipid signaling molecules that are synthesized in most mammalian tissues. Arachidonic acid, a major fatty acid precursor for prostanoids, is released from membrane phospholipids by phospholipase A2 and then converted to prostaglandin H2 (PGH2) by cyclooxygenase catalyzing a bisoxygenation and a net two-electron reduction with the release of water. PGH2 is considered to be transient and quickly converted to various bioactive prostanoids by isomerization or reduction with cell-specific so-called downstream enzymes. Biochemical and structural studies of prostanoid biosynthesis enzymes have been mainly focused on unveiling respective enzymatic features rather than collective terms. A comparative approach is attempted in this study with an aim of understanding about ligand-protein/protein-protein interactions of prostanoid biosynthesis-related enzymes. Proteins often experience conformational change upon ligand binding, which can be traced with a careful pairwise examination of the three-dimensional structures between unbound and ligand-complexed. Furthermore, computational solvent mapping to identify binding hot spots of a protein can suggest possible druggability providing fragment-based drug design. Cyclooxygenase has been previously investigated in detail for obtaining a clue for its characteristic behavior such as half-of-the-site activity. This paper describes individual and collective ligand-binding properties of the downstream enzymes based on an analysis of virtual docking experiments.