Research Papers

Journal of Computer-Aided Molecular Design

, Volume 7, Issue 1, pp 23-43

First online:

GenStar: A method for de novo drug design

  • Sergio H. RotsteinAffiliated withVertex Pharmaceuticals Incorporated
  • , Mark A. MurckoAffiliated withVertex Pharmaceuticals Incorporated

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A novel method, which we call GenStar, has been developed to suggest chemically reasonable structures which fill the active sites of enzymes. The proposed molecules provide good steric contact with the enzyme and exist in low-energy conformations. These structures are composed entirely of sp3 carbons which are grown sequentially, but which can also branch or form rings. User-selected enzyme seed atoms may be used to determine the area in which structure generation begins. Alternatively, GenStar may begin with a predocked ‘inhibitor core’ from which atoms are grown. For each new atom generated by the program, several hundred candidate positions representing a range of reasonable bond lengths, bond angles, and torsion angles are considered. Each of these candidates is scored, based on a simple enzyme contact model. The selected position is chosen at random from among the highest scoring cases. Duplicate structures may be removed using a variety of criteria. The compounds may be energy minimized and displayed using standard modeling programs. Also, it is possible to analyze the collection of all structures created by GenStar and locate binding motifs for common fragments such as benzene and naphthylene. Tests of the method using HIV protease, FK506 binding protein (FKBP-12) and human carbonic anhydrase (HCA-II) demonstrated that structures similar to known potent inhibitors may be generated with GenStar.

Key words

Drug design Protein structure Drug-ligand interactions HIV protease inhibitors Carbonic anhydrase inhibitors Ligand design Protein active site Enzyme inhibitors FKBP-12 inhibitors