Design of new selective inhibitors of cyclooxygenase-2 by dynamic assembly of molecular building blocks.

A method of dynamically assembling molecular building blocks - DycoBlock - has been proposed and tested by Liu et al. This method is based on multiple-copy stochastic dynamics simulation in the presence of a receptor molecule. In this method, a novel algorithm was used to dynamically assemble the molecular building blocks to form candidate compounds. Currently, some new improvements have been incorporated into DycoBlock to make it more efficient. In the new version of DycoBlock, the binding energy and solvent accessible surface area (SASA) can be used to screen the resulting compounds. A simple clustering algorithm based on molecular similarity was developed and used to classify the remaining compounds. The revised DycoBlock was tested by breaking SC-558 - a selective inhibitor of cyclooxygenase-2 (COX-2) - into building blocks and reassembling them in the active site of the enzyme. The accuracy of recovery grew to 58.8% while it was only 16.7% in the previous version. Then, thirty-three kinds of molecular building blocks were used in the design of novel inhibitors and the investigation of diversity. As a result, a total of 1441 compounds was generated with high diversity. After the first screening procedure, there remained 864 reasonable compounds. The results from clustering indicate that the structural motifs in the diarylheterocycle class of COX-2-selective inhibitors have been generated using the revised DycoBlock, and their binding modes were investigated.