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Persistence of camptothecin analog-topoisomerase I-DNA ternary complexes: a molecular dynamics study.
J Am Chem Soc. 2008 Dec 31; 130(52):17928-37.JA
Topoisomerase I (top1) is the sole chemotherapeutic target for the anticancer alkaloid camptothecin and its analogs (CPTs). The CPTs mediate cytotoxicity by binding reversibly to transient top1-DNA covalent complexes. There is significant variation in the persistence of the resultant CPTs-top1-DNA ternary complexes formed. Presently, there is no reliable method that can be used to predict the persistence of the ternary complexes, significantly limiting formulation of structure-activity relationships. Here, we used molecular dynamics simulations to probe the properties of several CPTs that form ternary complexes of greatly variable persistence. Our study reveals that correlated motions primarily occur between the CPTs and the flanking base pairs. We envision that the nature and strength of the interactions between the CPTs and the flanking base pairs are of key importance and can shed light on the mechanistic basis for the differing persistence of the ternary complexes. Our 'flanking base pairs' models further reveal that the most persistent CPTs (i) have higher calculated free-energy barriers for drug dissociation from the flanking base pairs, (ii) are less sensitive to changes in the rotation angles of the flanking base pairs, (iii) form stronger van der Waals and hydrophobic interactions, and (iv) have larger stacking areas with the flanking base pairs. Collectively, our study demonstrates that molecular dynamics simulations can be used to gain mechanistic insight into the molecular basis for the persistence of the ternary complexes and predict the persistence of such complexes during the drug discovery process.
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Siu FM
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China.
Che CM
No affiliation info available
Antineoplastic Agents, PhytogenicCamptothecinComputer SimulationDNADNA Topoisomerases, Type IEnzyme InhibitorsModels, MolecularStatic ElectricityThermodynamicsTopoisomerase I Inhibitors
Pub Type(s)
Siu, Fung-Ming, and Chi-Ming Che. "Persistence of Camptothecin Analog-topoisomerase I-DNA Ternary Complexes: a Molecular Dynamics Study." Journal of the American Chemical Society, vol. 130, no. 52, 2008, pp. 17928-37.
Siu FM, Che CM. Persistence of camptothecin analog-topoisomerase I-DNA ternary complexes: a molecular dynamics study. J Am Chem Soc. 2008;130(52):17928-37.
Siu, F. M., & Che, C. M. (2008). Persistence of camptothecin analog-topoisomerase I-DNA ternary complexes: a molecular dynamics study. Journal of the American Chemical Society, 130(52), 17928-37. https://doi.org/10.1021/ja806934y
Siu FM, Che CM. Persistence of Camptothecin Analog-topoisomerase I-DNA Ternary Complexes: a Molecular Dynamics Study. J Am Chem Soc. 2008 Dec 31;130(52):17928-37. PubMed PMID: 19035632.
TY - JOUR T1 - Persistence of camptothecin analog-topoisomerase I-DNA ternary complexes: a molecular dynamics study. AU - Siu,Fung-Ming, AU - Che,Chi-Ming, PY - 2008/11/28/pubmed PY - 2009/1/27/medline PY - 2008/11/28/entrez SP - 17928 EP - 37 JF - Journal of the American Chemical Society JO - J Am Chem Soc VL - 130 IS - 52 N2 - Topoisomerase I (top1) is the sole chemotherapeutic target for the anticancer alkaloid camptothecin and its analogs (CPTs). The CPTs mediate cytotoxicity by binding reversibly to transient top1-DNA covalent complexes. There is significant variation in the persistence of the resultant CPTs-top1-DNA ternary complexes formed. Presently, there is no reliable method that can be used to predict the persistence of the ternary complexes, significantly limiting formulation of structure-activity relationships. Here, we used molecular dynamics simulations to probe the properties of several CPTs that form ternary complexes of greatly variable persistence. Our study reveals that correlated motions primarily occur between the CPTs and the flanking base pairs. We envision that the nature and strength of the interactions between the CPTs and the flanking base pairs are of key importance and can shed light on the mechanistic basis for the differing persistence of the ternary complexes. Our 'flanking base pairs' models further reveal that the most persistent CPTs (i) have higher calculated free-energy barriers for drug dissociation from the flanking base pairs, (ii) are less sensitive to changes in the rotation angles of the flanking base pairs, (iii) form stronger van der Waals and hydrophobic interactions, and (iv) have larger stacking areas with the flanking base pairs. Collectively, our study demonstrates that molecular dynamics simulations can be used to gain mechanistic insight into the molecular basis for the persistence of the ternary complexes and predict the persistence of such complexes during the drug discovery process. SN - 1520-5126 UR - https://www.unboundmedicine.com/medline/citation/19035632/Persistence_of_camptothecin_analog_topoisomerase_I_DNA_ternary_complexes:_a_molecular_dynamics_study_ L2 - https://doi.org/10.1021/ja806934y DB - PRIME DP - Unbound Medicine ER -
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Camptothecin
DNA Topoisomerases, Type I
Topoisomerase I Inhibitors
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