J Comput Aided Mol Des. 1999 Sep;13(5):513-32. Unique Identifier :
We present a set of programs, DREAM+2 (Docking and Reaction programs
using Efficient seArch Methods written in C++), for docking
computationally generated ligands into macromolecular binding sites.
DREAM++ is composed of three programs: ORIENT++, REACT++ and SEARCH++.
The program ORIENT++ positions molecules in a binding site with the DOCK
algorithm. Its output can be used as input to REACT++ and SEARCH+2. The
program REACT++ performs user-specific chemical reactions on a docked
molecule, so that reaction products can be evaluated for three
dimensional complementarity with the macromolecular site. The program
SEARCH++ performs an efficient conformation search on the reaction
products using a hybrid backtrack and incremental construction
algorithm. We have applied the programs to HIV protease-inhibitor
complexes as test systems. We found that we can differentiate
high-affinity ligands based on several measures: interaction energies,
occupancy of protein subsites and the number of successfully docked
conformations for each product. Encouraged by the results in the test
case, we applied the programs to propose novel inhibitors of HIV
protease. These inhibitors can be generated by organic reactions using
commercially available reagents. They are alternatives to the inhibitors
synthesized by Glaxo.
JOURNAL ARTICLE Algorithms Binding Sites Cluster Analysis *Computer
Simulation *Drug Design HIV Protease Inhibitors/CHEMISTRY/METABOLISM
Ligands Penicillins/CHEMISTRY/METABOLISM Support, U.S. Gov't, P.H.S.