Background Cyclooxygenase-1 and -2 (COX-1/COX-2) catalyse the rate-limiting step in prostaglandin (PG) synthesis and are the targets of non-steroidal anti-inflammatory drugs (NSAIDs). The evidence is strong that the selective COX-2 inhibitors have reduced GI side effects in patients treated for rheumatic conditions, including osteoarthritis.
Objectives The molecular basis of binding affinities and COX-2/COX-1 selectivity are explored using an approach that combines experimental results from X-ray analyses and docking experiments from computational chemistry.
Methods The reported X-ray structures of COX-1 and COX-2 were used for computational optimisation of the interaction between the different NSAIDs and COX isoforms using the established computer program Sybyl/Molcad.
Results The inhibition of COX can occur by compounds with high degree of structural diversity and various types of mechanisms. The results show that COX-2 selective inhibitors are belonging to several different, structural distinct classes: arylalkanoic acids, enolcarboxamids, acidic sulfonamids and diarylheterocycles.
Two fundamental differences between the active site of COX-2 and COX-1 are responsible for the COX-2 selectivity and are caused by several amino acid substitution in COX-2 vs. COX-1: The volume of the COX-2 channel is extended by the substitution of Iso 523 by Val 523, Iso 434 by Val 434, His 513 by Arg 513 and Phe 503 by Leu 503.
COX-selective diaryl-heterocycles (DuP 697, celecoxib, rofecoxib) are exploiting the side pocket and enolcarboxamid (meloxicam) and acidic sulfonamids (L745,733, NS 398, nimesulide) the extra space at the top of the channel.
Conclusion This work illustrates the value of novel docking procedure for determining the binding of NSAIDs to the COX-enzyme. The structural insights into the binding mechanism indicate that COX-2 selectivity can be obtained by at least three chemically distinct classes of NSAIDs of which meloxicam, nimesulide and celecoxib are representatives.
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