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Article: Persistence of camptothecin analog - topoisomerase I - DNA ternary complexes: A molecular dynamics study

TitlePersistence of camptothecin analog - topoisomerase I - DNA ternary complexes: A molecular dynamics study
Authors
Issue Date2008
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.html
Citation
Journal Of The American Chemical Society, 2008, v. 130 n. 52, p. 17928-17937 How to Cite?
AbstractTopoisomerase 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. © 2008 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/58346
ISSN
2015 Impact Factor: 13.038
2015 SCImago Journal Rankings: 7.123
ISI Accession Number ID
Funding AgencyGrant Number
University Grants Committee of the Hong Kong Special Administrative Region, ChinaAoE/P-10/01
Committee on Research and Conference (CRCR)
University Development Fund
Funding Information:

This work was supported by the Areas of Excellence Scheme administered by the University Grants Committee of the Hong Kong Special Administrative Region, China (AoE/P-10/01). The small project funding granted to Fung-Ming Siu by the Committee on Research and Conference Grants (CRCR) and University Development Fund granted to Chi-Ming Che are gratefully acknowledged. We thank Dr. Rory Watt for his help editing this manuscript.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorSiu, FMen_HK
dc.contributor.authorChe, CMen_HK
dc.date.accessioned2010-05-31T03:28:42Z-
dc.date.available2010-05-31T03:28:42Z-
dc.date.issued2008en_HK
dc.identifier.citationJournal Of The American Chemical Society, 2008, v. 130 n. 52, p. 17928-17937en_HK
dc.identifier.issn0002-7863en_HK
dc.identifier.urihttp://hdl.handle.net/10722/58346-
dc.description.abstractTopoisomerase 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. © 2008 American Chemical Society.en_HK
dc.languageengen_HK
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/journals/jacsat/index.htmlen_HK
dc.relation.ispartofJournal of the American Chemical Societyen_HK
dc.titlePersistence of camptothecin analog - topoisomerase I - DNA ternary complexes: A molecular dynamics studyen_HK
dc.typeArticleen_HK
dc.identifier.emailSiu, FM:fmsiu@hku.hken_HK
dc.identifier.emailChe, CM:cmche@hku.hken_HK
dc.identifier.authoritySiu, FM=rp00776en_HK
dc.identifier.authorityChe, CM=rp00670en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1021/ja806934yen_HK
dc.identifier.pmid19035632-
dc.identifier.scopuseid_2-s2.0-58849133822en_HK
dc.identifier.hkuros155388en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-58849133822&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume130en_HK
dc.identifier.issue52en_HK
dc.identifier.spage17928en_HK
dc.identifier.epage17937en_HK
dc.identifier.eissn1520-5126-
dc.identifier.isiWOS:000263320900050-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectInstitute of molecular technology for drug discovery and synthesis-
dc.identifier.scopusauthoridSiu, FM=6701518489en_HK
dc.identifier.scopusauthoridChe, CM=7102442791en_HK
dc.identifier.citeulike3768166-

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