Validation of the SPROUT de novo design program

The validation of SPROUT was carried out on four receptor-ligand complexes: thrombin-NAPAP, calmodulin (CAM)AAA, Ras P-21-GDP and dihydrofolate reductase (DHFR)-methotrexate (MTX). These complexes were downloaded from the Brookhaven Protein Data Bank (PDB). For the thrombin-NAPAP complex, two structures very similar to NAPAP were generated. These two structures were similar in 3D structure to NAPAP but contained an extra hexane ring. For CAM-AAA and Ras P-21-GDP, the ligands generated were essentially identical to their original ligands. For DHFR, two ligands, one most similar in 2D structure and one most similar in 3D conformation were found. The successful regeneration of the ligands for each case proves the ability and applicability of SPROUT for designing strongly binding, successful drug candidates. When the program is executed with less restricted constraints, it generates a large number of novel structures that are structurally diverse, making it an ideal tool for de novo design. (C) 2003 Elsevier B.V. All rights reserved.