Rational procedure for 3D-QSAR analysis using TRNOE experiments and computational methods: application to thermolysin inhibitors

The success or failure of 3D QSAR, particularly CoMFA, is most strongly dependent, especially for flexible compounds, on the conformation of the molecule used in the analysis, and on the orientation of the molecule relative to the other molecules in 3D space (i.e., alignment). The present study suggests a rational procedure for the estimation of binding conformation that uses the transferred nuclear Overhauser effect (TRNOE) experiment in combination with conformational analysis using CAMDAS (Conformational Analyzer with Molecular Dynamics And Sampling) program that is developed in our laboratory. In the next step the TRNOE-obtained conformation can be used as a reference template in order to obtain alignment of other ligands, that have a common binding site. In this step we used the SUPERPOSE program created in our laboratory, in order to estimate the binding conformation of other compounds, and to simultaneously obtain the alignment of compounds for CoMFA. The resulting CoMFA models could be expected to closely reproduce the interaction mode with protein represented by the reported X-ray results. In order to confirm the validity of our procedure described above, we show its application in obtaining CoMFA models of thermolysin inhibitors. We obtained twenty CoMFA models, and that with the highest q2 value (q2 = 0.701) was found to provide an interaction mode very similar to that represented by the X-ray results.