GroupBuild: a fragment-based method for de novo drug design.
A novel method for de novo drug design, GroupBuild, has been developed to suggest chemically reasonable structures which fill the active sites of enzymes. The proposed molecules provide good steric and electrostatic contact with the enzyme and exist in low-energy conformations. These structures are composed entirely of individual functional groups (also known as "building blocks" or "fragments") which the program chooses from a predefined library. User-selected enzyme seed atom(s) may be used to determine the area(s) in which structure generation begins. Alternatively, GroupBuild may begin with a predocked "inhibitor core" from which fragments are grown. For each new fragment generated by the program, several thousand candidates in a variety of locations and orientations are considered. Each of these candidates is scored based on a standard molecular mechanics potential function. The selected fragment and orientation are chosen from among the highest scoring cases. Tests of the method using HIV protease, FK506 binding protein, and human carbonic anhydrase demonstrate that structures similar to known potent inhibitors may be generated with GroupBuild.
Rotstein
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Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139-4211.
Murcko
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D001483:Base Sequence; D001665:Binding Sites; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry; D002256:Carbonic Anhydrases / Q000737:chemistry; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D015195:Drug Design; D004563:Electrochemistry; D004791:Enzyme Inhibitors / Q000737:chemistry*; D004798:Enzymes / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000737:chemistry; D012984:Software; D022021:Tacrolimus Binding Proteins
D002257:Carbonic Anhydrase Inhibitors; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D004798:Enzymes; D011480:Protease Inhibitors; D016333:HIV Protease; D002256:Carbonic Anhydrases; D022021:Tacrolimus Binding Proteins