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 inhibitor...

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Bibliographic Details
Published in:	Journal of medicinal chemistry Vol. 38; no. 3; pp. 466 - 472
Main Authors:	Gehlhaar, Daniel K, Moerder, Karl E, Zichi, Dominic, Sherman, Christopher J, Ogden, Richard C, Freer, Stephan T
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 01-02-1995
Subjects:	AIDS/HIV Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Biological and medical sciences Drug Design Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - metabolism Folic Acid Antagonists HIV Protease Inhibitors - chemical synthesis HIV Protease Inhibitors - metabolism HIV-1 - enzymology Ligands Medical sciences Monte Carlo Method Pharmacology. Drug treatments Substrate Specificity Thymidylate Synthase - antagonists & inhibitors Monte Carlo method HIV-1 virus Enzyme Ligand Transferases Retroviridae Enzyme inhibitor Molecular interaction Binding site Thymidylate synthase Modeling De novo Virus Methyltransferases Simulation Molecular model Binding mode Hydrolases Lentivirinae Antiviral Oxidoreductases Human immunodeficiency virus Dihydrofolate reductase Proteinases
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Summary:	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.
Bibliography:	istex:59E2CF3CECC72BD92283501DE424BF306F478408 ark:/67375/TPS-HM14JR5H-0 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm00003a010