Abstract
This presentation focuses upon developing methods to postulate active conformations/shapes in a series of flexible analogs when the receptor geometry is unknown. In one study of a set of 3-X substituted triazines which inhibit dihydrofolate reductase (DHFR), the size and flexibility of the substituents were both too large, and the number of analogs and substituent structural changes each too small, to permit a reliable inference of the active substituent conformation. However, use of template conformations from ligands bound to DHFR, along with minimum energy substituent conformations, permitted us to postulate that the bonding topology of the substituent, and not its conformation, controls the SAR. In another study of a series of β-hydroxylase inhibitors it was possible to construct a molecular shape descriptor that employs loss in intramolecular conformational energy as part of the shape comparison. In both cases significant 3D-QSARs were generated and the methods developed were added to our molecular shape analysis (MSA) formalism.
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© 1992 Springer-Verlag Berlin Heidelberg
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Burke, B.J., Rowberg, K., Cardozo, M.G., Koehler, M.G., Hopfinger, A.J. (1992). New Methods in Molecular Shape Analysis to Identify and Characterize Active Conformations. In: Shugar, D., Rode, W., Borowski, E. (eds) Molecular Aspects of Chemotherapy. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-02740-0_2
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DOI: https://doi.org/10.1007/978-3-662-02740-0_2
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