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].