DREAM++: Flexible docking program for virtual combinatorial libraries

We present a set of programs, DREAM++ (Docking and Reaction programs using Efficient seArch Methods written in C++), for docking computationally gener ated ligands into macromolecular binding sites. DREAM++ is composed of thre e programs: ORIENT++, REACT++ and SEARCH++. The program ORIENT++ positions molecules in a binding site with the DOCK algorithm [1, 2]. Its output can be used as input to REACT++ and SEARCH++. The program REACT++ performs user -specified chemical reactions on a docked molecule, so that reaction produc ts can be evaluated for three dimensional complementarity with the macromol ecular site. The program SEARCH++ performs an efficient conformation search on the reaction products using a hybrid backtrack [3, 4] and incremental c onstruction [5, 6] algorithm. We have applied the programs to HIV protease- inhibitor complexes as test systems. We found that we can differentiate hig h-affinity ligands based on several measures: interaction energies, occupan cy of protein subsites and the number of successfully docked conformations for each product. Encouraged by the results in the test case, we applied th e programs to propose novel inhibitors of HIV protease. These inhibitors ca n be generated by organic reactions using commercially available reagents. They are alternatives to the inhibitors synthesized by Glaxo [7, 8].