Conformational analysis of folates and folate analogues

M Joy Spark, David Winkler, Peter R Andrews

Research output: Contribution to journalArticleResearchpeer-review

15 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)321-333
Number of pages13
JournalInternational Journal of Quantum Chemistry
Volume22
Issue numberS9
DOIs
Publication statusPublished - 1982
Externally publishedYes

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