| Rational drug design is a critical step in pharmaceutical industry. The development of computer hardware and software make it possible to rationally design new drug with computer-aided drug design (CADD), CADD contribute not only to the design of potent compounds, but to many of the steps of going "from concept to clinic". In this thesis, we studied several projects by CADD as follows.1. Structure-Based Design of Selective Cyclooxygenase-2 (COX-2) InhibitorsThe discovery of COX-2 provided a new target for the design of nonsteroidal anti-inflammatory Drugs (NSAIDs) with less side effects. In order to disclose the relationship between the activity and structure, the studies contained four aspects:(1)A series of 44 selective COX-2 inhibitors were investigated with the aim of developing a 3D-QSAR model using the comparative molecular field analysis (CoMFA). The active conformation was extracted from the SC-558/COX-2 complex but the alignment of the molecule was performed through two approaches, one is atom to atom operation, the other is determined by DOCK. The model from DOCK alignment shows higher ability to explain and predict the activity of selective COX-2 inhibitor than the model from the classical atom to atom alignment. The feature of this 3D-model are consistent with the binding pocket. According to the model derived from DOCK-based CoMFA, six classes of inhibitors of COX-2 were designed, five of which have been synthesized and their activities assay are being tested.(2)By using DOCK program, the relationship between activity and binding energy for tricycle inhibitors, NS-398 analogues and Indomethacin was constructed. In addition, DOCK mimics the binding of NS-398 analogues to COX-2, and the results indicated that NS-398 analogues possess higher activity because of the presence of additional hydrogen-bondings.(3) In order to understand the specificity of COX-2 and COX-1, selective COX-2 and non-selective inhibitors were docked into COX-1 and COX-... |
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