Molecular dynamics simulation of the interaction of 5-keto substituted 7-tert-butyl-2,3-dihydro-3,3- dimethylbenzofuran derivatives with cyclooxygenase-2

We present here results on molecular dynamics simulation of three 7-tert-butylbenzofurans with substituents at the fifth position: CONH(CH2)2OMe (BF1), CONH-c-Pr(cyclopropyl) (BF2) and 3-methylene-γ-butyrolactonyl (BF3), complexed with cyclooxygenase-2 (COX-2), a target for non-steroidal anti-inflammatory drugs (NSAIDs). Perturbative changes in the enzyme structure, energetics of interaction and points of contact are monitored. Our results showed that difference in root mean square deviations (RMSDs) of backbone Cα atoms in interdomain contact and heme binding loops, better interaction with adjoining helical segments, H-bonding and electrostatic interaction with Arg120, Tyr355, Arg513, His90 and more ‘relaxed conformation’ at the channel entrance led to better COX-2 selectivity by BF1. Hydrophobic contacts with Met113, Pro86 and Val89 increase COX-2 selectivity. Higher potency of BF3 is due to its better interaction with membrane-anchoring region of COX-2 and larger mobility of residues in the cavity.