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Conformational analysis of folates and folate analogues
Author(s) -
Spark M. J.,
Winkler D. A.,
Andrews P. R.
Publication year - 2009
Publication title -
international journal of quantum chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.484
H-Index - 105
eISSN - 1097-461X
pISSN - 0020-7608
DOI - 10.1002/qua.560220730
Subject(s) - dihydrofolate reductase , pteridine , chemistry , ring (chemistry) , molecule , stereochemistry , computational chemistry , antifolate , crystallography , enzyme , biochemistry , antimetabolite , organic chemistry , toxicity
Conformational energy calculations have been performed on a series of folates and folate analogues, including dihydrofolate and methotrexate. A large number of conformations are energetically accessible to these molecules, and some are common to all. The conformations adopted by methotrexate, when bound to dihydrofolate reductases from various sources, are available from crystal structures. These conformations are of surprisingly high energy relative to the global minimum. Conformational energy calculations were also used to test the proposition that the pteridine ring of dihydrofolate may bind upside down with respect to that of methotrexate. Superimposition of low energy conformations of dihydrofolate on the bound conformations of methotrexate demonstrates that a reasonable match may be achieved with the pteridine ring upside down. Electrostatic potential calculations show that these conformations fit into the binding cavity of dihydrofolate reductase in a way that permits favorable nonbonded interactions.