Conformational behaviour of the antineoplastic peptide dolastatin-10 and of two mutated derivatives |
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Authors: | Piercarlo Fantucci Tiziana Marino Nino Russo Anna Maria Villa |
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Institution: | (1) Dip. di Chimica Inorganica, Università di Milano, Centro CNR, via Venezian 21, I-20133 Milan, Italy;(2) Dip. di Chimica, Università della Calabria, Arcavacata di Rende, I-87036 Cosenza, Italy;(3) Ist. di Chimica Farmaceutica e Tossicologica, Università di Milano, viale Abruzzi 42, I-20131 Milan, Italy |
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Abstract: | Summary The three-dimensional structure of dolastatin-10, an extremely potent cytostatic and antineoplastic peptide extracted from the mollusc Dolabella auricularia, has not yet been fully characterized in an experimental way. By means of a systematic conformational search of the natural peptide and of two mutated analogs, carried out both in vacuo and in aqueous solution, the present work allows to obtain insights into the conformational preferences of this remarkable compound. In addition, the ability to form intra- and intermolecular H-bonds as a function both of the sequence and of the conformation is discussed. The search for the best molecular conformations has been carried out using a molecular mechanics approach, based on the CVFF potential. Dolastatin-10 contains some unusual amino acids for which no experimental structural data are available. In order to check the reliability of the CVFF potential in predicting structures of such nonconventional amino acids, geometry optimizations have been carried out using the ab initio Hartree-Fock procedure. The CVFF parameterization is found to be adequate also for nonconventional amino acids. |
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Keywords: | Cytostatic compounds Tubulin Mitosis inhibitors Quenching Ab initio optimization Unusual amino acids Conformational search |
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