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An amber compatible molecular mechanics force field for the anticancer drug topotecan

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Abstract

A molecular mechanics (MM) force field has been developed for the topotecan (TPT) molecule, an anticancer drug the only molecular target of which is the human topoisomerase I-DNA covalent complex. We proceeded according to the amber03 force field parametrization protocol, based on quantum mechanical calculations with solvent effects included by means of continuum models. An adequate description of the electronic states of TPT has been ensured comparing calculated IR vibrational frequencies and NMR chemical shifts with experimental results. Bonded molecular parameters have been verified by comparison with ab initio normal mode vibrational analysis, while atomic charges have been fitted either using the restrained electrostatic potential fitting (RESP) or the multi-conformational RESP (MultiRESP) procedures. Particular attention has been paid to the parametrization of the dimethylamino group in ring A, for which several energy minima were found. The reliability of the force field has been checked comparing the results obtained from a classical molecular dynamics simulation with quantum mechanics ab initio energy calculations. The development of the topotecan force field makes it possible to carry out reliable simulations of the topotecan–topoisomerase–DNA ternary complex, thus allowing the investigation of important biological questions, such as the selective resistance to topotecan caused by single residue topoisomerase I mutations.

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Acknowledgments

The authors would like to thank C. Zazza for his contribution to data analysis and comments, and Prof. Jens Z. Pedersen for help in revising the manuscript. This work was partly supported by grants ‘Characterization of human topoisomerase I mutants resistant to camptothecin and its derivatives’ from AIRC (Associazione Italiana Ricerca Cancro) to A. D. and FILAS-Lazio regional agency under the project CAMPTOFAR. We acknowledge CASPUR Supercomputing Consortium for computational resources.

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Authors and Affiliations

  1. CASPUR Interuniversities Consortium for Supercomputing Applications, Via dei Tizii 6b, 00185, Rome, Italy

    Giovanni Chillemi, Giordano Mancini & Nico Sanna

  2. Department of Biology, University of Rome Tor Vergata, Via Della Ricerca Scientifica, 00133, Rome, Italy

    Andrea Coletta & Alessandro Desideri

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  1. Giovanni Chillemi
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  2. Andrea Coletta
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Correspondence to Giovanni Chillemi.

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Chillemi, G., Coletta, A., Mancini, G. et al. An amber compatible molecular mechanics force field for the anticancer drug topotecan. Theor Chem Acc 127, 293–302 (2010). https://doi.org/10.1007/s00214-009-0715-9

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