De novo design of enzyme inhibitors by Monte Carlo ligand generation.
A new computational method for the in situ generation of small molecules within the binding site of a protein is described. The method has been evaluated using two well-studied systems, dihydrofolate reductase and thymidylate synthase. The method has also been used to guide improvements to inhibitors of HIV-1 protease. One such improvement resulted in a compound selected for preclinical studies as an antiviral agent against AIDS.
Gehlhaar
D K
DK
Agouron Pharmaceuticals, Inc., San Diego, California 92121.
Moerder
K E
KE
Zichi
D
D
Sherman
C J
CJ
Ogden
R C
RC
Freer
S T
ST
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism; D005493:Folic Acid Antagonists; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology; D008024:Ligands; D009010:Monte Carlo Method; D013379:Substrate Specificity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D017320:HIV Protease Inhibitors; D008024:Ligands; D013940:Thymidylate Synthase