Structural and Chemical Biology of the Interaction of Cyclooxygenase with Substrates and Non-Steroidal Anti-Inflammatory Drugs

Abstract

Cyclooxgenases are key enzymes of lipid signaling. They carry out the first step in the production of prostaglandins, important mediators of inflammation, pain, cardiovascular disease, and cancer, and they are the molecular targets for nonsteroidal anti-inflammatory drugs, which are among the oldest and most chemically diverse set of drugs known. Homodimeric proteins that behave as allosterically modulated, functional heterodimers, the cyclooxygenases exhibit complex kinetic behavior, requiring peroxide-dependent activation and undergoing suicide inactivation. Due to their important physiological and pathophysiological roles and keen interest on the part of the pharmaceutical industry, the cyclooxygenases have been the focus of a vast array of structural studies, leading to the publication of over 80 crystal structures of the enzymes in complex with substrates or inhibitors supported by a wealth of functional data generated by site-directed mutation experiments. In this review, we explore the chemical biology of the cyclooxygenases through the lens of this wealth of structural and functional information. We identify key structural features of the cyclooxygenases, break down their active site into regional binding pockets to facilitate comparisons between structures, and explore similarities and differences in the binding modes of the wide variety of ligands (both substrates and inhibitors) that have been characterized in complex with the enzymes. Throughout, we correlate structure with function whenever possible. Finally, we summarize what can and cannot be learned from the currently available structural data and discuss the critical intriguing questions that remain despite the wealth of information that has been amassed in this field.

Protective Effects of Caesalpinia sappan Linn. and Its Bioactive Compounds on Cardiovascular Organs

“…Cyclooxygenase is an enzyme that synthesizes prostaglandin from arachidonic acid. Prostaglandin itself is a strong vasodilator, which is also converted into products such as thromboxane, a vasoconstrictor, and prostacyclin, a vasodilator ( Rouzer and Marnett, 2020 ). Therefore, brazilin may augment the production of prostaglandin which then promotes vasodilation.…”

The Role of Organic Small Molecules in Pain Management

“…The main target of anti-inflammatory drugs (NSAIDs) is the cyclooxygenase (COX) pathway composed of two isoforms of the enzyme, i.e., cyclooxygenase-1 (COX-2) and cyclooxygenase-2 (COX-2). Both isoforms have an alpha carbon RMSD of only 0.9 Å. Cyclooxygenases are key in the lipid signaling pathway, being the first and rate-dependent step in prostaglandin and thromboxane synthesis [ 24 , 25 ]. Therefore, NSAIDs work by inhibiting the COX pathway and preventing the synthesis of prostaglandins [ 1 ].…”

“…Structural and functional information about COXs has been widely studied, identifying structural features key for binding [ 25 ] and using different techniques such as saturation transfer difference NMR spectroscopy (STD) [ 38 ]. To fit the active site, the basis of an NSAID chemical structure is generally composed of an aromatic ring and an acidic group.…”

Recent Advances in the Synthesis of Ibuprofen and Naproxen

“…As NSAIDs prevail as pain relievers, they have become highly popular drugs in the pharmaceutical market. Their large market has forced the pharmaceutical community to discover advanced synthesis routes for NSAID skeletons [ 14 , 15 , 16 ]. From a structural viewpoint, NSAIDs skeletons are usually classified as being an aromatic acetic acid or propionic acid skeleton that contains an additional chiral center.…”