Transition state structure of 5′-methylthioadenosine/s-adenosylhomocysteine nucleosidases
AssigneeAlbert Einstein College of Medicine of Yeshiva University
InventorVern L. Schramm
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Abstract
Provided are methods of designing a putative inhibitor of a 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase. The methods comprise designing a chemically stable compound that resembles the charge and geometry of the 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase transition state. Also provided are methods of inhibiting 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidases using the inhibitors found by the above methods.
Claims20
A method of screening for an inhibitor of a 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) having 5′methylthioadenosine and S-adenosylhomocysteine substrates, the method comprising the steps of:
- (i) measuring kinetic isotope effects on the MTAN catalyzed hydrolysis of 5′-methylthioadenosine to obtain the MTAN transition state structure,
- wherein the MTAN transition state comprises the structure
- where R is CH3 or homocysteine;
- (ii) determining the molecular electrostatic potential at the van der Waals surface computed from the wave function of the MTAN transition state and the geometric atomic volume of the MTAN transition state;
- (iii) obtaining a chemically stable compound that resembles the molecular electrostatic potential at the van der Waals surface computed from the wave function of the MTAN transition state and the geometric atomic volume of the MTAN transition state,
- wherein the compound comprises a moiety resembling the molecular electrostatic potential surface of the ribosyl group at the transition state,
- wherein the moiety resembling the molecular electrostatic potential surface of the ribosyl group at the transition state is a substituted iminoribitol, a substituted hydroxypyrrolidine, a substituted pyridine or a substituted imidazole,
- wherein the compound comprises an atomic moiety inserted into the inhibitor providing a compound that mimics the C1′-N9 ribosyl bond distance of a 5′-methylthioadenosine or S-adenosylhomocysteine at the transition state,
- wherein the atomic moiety inserted into the inhibitor that provides a compound that mimics the C1′-N9 ribosyl bond distance of a 5′-methylthioadenosine or S-adenosylhomocysteine at the transition state is a methylene, a substituted methylene, an ethyl, or a substituted ethyl bridge, and
- wherein the compound comprises a purine moiety or a deazapurine moiety;
- and
- (iv) testing the compound for inhibitory activity to MTAN by determining if the compound inhibits MTAN-catalyzed hydrolysis of 5′-methylthioadenosine to generate adenine and 5-methylthioribose or if the compound inhibits MTAN-catalyzed hydrolysis of S-adenosylhomocysteine to generate adenine and S-ribosylhomocysteine,
- wherein a compound that inhibits MTAN-catalyzed hydrolysis of 5′-methylthioadenosine or S-adenosylhomocysteine is an inhibitor of MTAN.
Dependencies are inferred from the claim text.