Abstract
The enormous magnitude of scientific research carried out in the field of NSAIDs and cyclooxygenases (COXs) is known. They are crucial in pain management. COX-2 inhibitors have evolved over the years; from traditional NSAIDs to isoform-specific. The present study is aimed to identify a cluster of amino acids in the catalytic site whose energy contribution can better explain COX-2 inhibitory activity accurately than the binding energy of the whole protein. Initially, MD simulations (25 ns) and MM-PBSA calculations were performed for 8 diarylheterocyclic inhibitors. Per-residue energy decomposition studies were carried out to elucidate the energy contribution of each amino acid, and their correlation with COX-2 inhibitory activity was enumerated. A cluster of catalytic amino acids whose free energy sum has a high correlation with biological data was identified. The cluster of Gln178, Ser339, Tyr341, Arg499, Phe504, Val509 and Ala513 showed the correlation of -0.60. Further, the study was extended to a total of 26 COX-2 inhibitors belonging to different classes to validate the applicability of the cluster of amino acids identified. Results clearly suggest that the cluster of amino acids identified provide accurate screening method, and can be applied to predict COX-2 inhibitory activity of small molecules.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a vital class of drugs that inhibit cyclooxygenases (COXs) [1]
A variety of COX-2 inhibitors belonging to different structural classes were considered
After molecular docking, detailed interaction analysis was performed to get insights into the amino acids involved in various interactions
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) constitute a vital class of drugs that inhibit cyclooxygenases (COXs) [1]. Traditional NSAIDs suppress the activities of both isoforms; the constitutive cytoprotective COX-1 and the inducible COX-2 This led to adverse GI toxicities [10, 11, 12]. The COX-2 binding site is extensively studied by various research groups and it has been found that His, Arg120, Tyr355, and Glu524 form a hydrogen bond network at the entrance of the binding site, known as gate residues [18] Other amino acids such as Arg513, Gln192, Phe518, Trp387, Tyr385, Tyr348, Leu359, Tyr355, Leu531, Ser530 and Leu534 (in PGHS-1 numbering) are present towards the interior of the active site [19]. The Molecular docking and simulation procedures followed are the same as discussed in our previous work [38], but for a better understanding of the readers, the same is presented in detail here
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