Computational determination of binding modes of 2-acetoxyphenylhept-2-ynyl sulfide to cyclooxygenase-2

2-Acetoxyphenylhept-2-ynyl sulfide (APHS) is a potent covalent inhibitor with cyclooxygenase-2 (COX-2) selectivity. However, no crystal structure for APHS‒COX-2 complex has been reported. In this work, we have extensively studied the binding modes and interactions between APHS and COX-2. Molecular docking followed by MD simulations identified a stable and reactive binding mode, of which the calculated binding free energy was in good agreement with the experimental reports. Furthermore, binding modes of six analogs of APHS were also analyzed to study the effects on binding affinity of the triple bond, heteroatom and length of alkyl chain. The findings help to understand the action mechanisms of APHS and explain why it is more potent than the analogs, which might be useful in the design of new compounds with higher inhibitory activity to COX-2. Communicated by Ramaswamy H. Sarma