Makino S, Ewing T J, Kuntz I D
Department of Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco 94143-0446, USA.
J Comput Aided Mol Des. 1999 Sep;13(5):513-32. doi: 10.1023/a:1008066310669.
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.
我们展示了一组程序，即DREAM+2（使用高效搜索方法用C++编写的对接与反应程序），用于将计算生成的配体对接至大分子结合位点。DREAM++由三个程序组成：ORIENT++、REACT++和SEARCH++。ORIENT++程序使用DOCK算法将分子定位在结合位点。其输出可作为REACT++和SEARCH+2的输入。REACT++程序对对接的分子进行用户特定的化学反应，以便评估反应产物与大分子位点的三维互补性。SEARCH++程序使用混合回溯和增量构建算法对反应产物进行高效的构象搜索。我们已将这些程序应用于HIV蛋白酶-抑制剂复合物作为测试系统。我们发现，基于多种指标可以区分高亲和力配体：相互作用能、蛋白质亚位点占有率以及每个产物成功对接的构象数量。受测试案例结果的鼓舞，我们应用这些程序来设计HIV蛋白酶的新型抑制剂。这些抑制剂可以通过使用市售试剂进行有机反应生成。它们是葛兰素公司合成的抑制剂的替代品。
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