Discovery of novel types of inhibitors of S-adenosylmethionine synthesis by virtual screening.
S-adenosylmethionine (AdoMet) lies at an intersection of nucleotide and amino acid metabolism and performs a multitude of metabolic functions. AdoMet formation is catalyzed by S-adenosylmethionine synthetase (ATP: L-methionine S-adenosyltransferase (MAT)), which is a target for development of anticancer and antimicrobial agents. High affinity MAT inhibitors have been found through computational docking of more than 200000 compounds for predicted binding to the crystallographically defined nucleotide binding region of the enzyme's active site. Two of the top scoring candidate compounds had IC(50) values less than 10 nM, more than 10000-fold lower than the substrates' K(M) values. The compounds are structurally unrelated to the natural ligands of the enzyme. The enzyme is protected from inhibition by ATP, but not by methionine, consistent with binding at the adenosyl region of the active site. These results validate in silico screening as a robust approach to the discovery of inhibitors of this chemotherapeutically relevant enzyme.
Taylor
John C
JC
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Bock
Charles W
CW
Takusagawa
Fusao
F
Markham
George D
GD
D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004926:Escherichia coli / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008716:Methionine Adenosyltransferase / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D011487:Protein Conformation; D012436:S-Adenosylmethionine / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D012441:Saccharomyces cerevisiae / Q000187:drug effects
D012436:S-Adenosylmethionine; D008716:Methionine Adenosyltransferase