In this paper we describe the search strategies developed for docking flexible molecules to macomolecular sites that are incorporated into the widely distributed DOCK software, version 4.0. The search strategies include incremental construction and random conformation search and utilize the existing Coulombic and Lennard-Jones grid-based scoring function. The incremental construction strategy is tested with a panel of 15 crystallographic testcases, created from 12 unique complexes whose ligands vary in size and flexibility. For all testcases, at least one docked position is generated within 2 A of the crystallographic position. For 7 of 15 testcases, the top scoring position is also within 2 A of the crystallographic position. The algorithm is fast enough to successfully dock a few testcases within seconds and most within 100 s. The incremental construction and the random search strategy are evaluated as database docking techniques with a database of 51 molecules docked to two of the crystallographic testcases. Incremental construction outperforms random search and is fast enough to reliably rank the database of compounds within 15 s per molecule on an SGI R10000 cpu.

No abstract

We report an efficient solid-phase synthesis of diverse 1,3N-disubstituted quinazoline-2,4-diones. Since substitutions at the 1N-position of quinazolidine-2,4-diones were introduced by reaction between primary amines and 2-fluoro-5-nitrobenzoyl amides (S N Ar reaction), substitutions that cannot be prepared by alkylation or arylation can be easily introduced. In addition, the nitro group of quinazoline-2,4-diones can be repeatedly reduced to provide 3N-amines for quinazoline-2,4-dione syntheses, allowing the synthesis of quinazoline-2,4-dione oligomers and polymers. An oligomer with four quinazoline-2,4-dione units was successfully synthesized.

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.