Molecular dynamics simulations and experimental studies of binding and mobility of 7-tert-butyldimethylsilyl-10-hydroxycamptothecin and its 20(S)-4-aminobutyrate ester in DMPC membranes.

Molecular dynamics simulations and experimental studies of binding and mobility of 7-tert-butyldimethylsilyl-10-hydroxycamptothecin and its 20(S)-4-aminobutyrate ester in DMPC membranes. Research Abstract Details 

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Molecular dynamics simulations and experimental studies of binding and mobility of 7-tert-butyldimethylsilyl-10-hydroxycamptothecin and its 20(S)-4-aminobutyrate ester in DMPC membranes. Abstract Text:

Tian-Xiang Xiang,Zhi-Qiang Jiang,Lin Song,Bradley D Anderson,

The enhanced permeability and retention of liposomes in solid tumors makes liposomal formulations attractive for the targeting of various antitumor agents. This study explores the binding, orientation, and dynamic properties of a potent topoisomerase I inhibitor, 7-tert-butyldimethylsilyl-10-hydroxycamptothecin (DB-67), and its 20(S)-4-aminobutyrate ester prodrug (DB-67-AB) in DMPC liposomes by molecular dynamics (MD) simulations and experimental studies. MD simulations of an all-atom and fully hydrated liquid-crystalline bilayer (2 x 36 DMPC lipids) containing single molecules of DB-67 and DB-67-AB were conducted for up to 50 ns. Membrane/water partition coefficients for DB-67 and DB-67-AB vs pH were determined by ultracentrifugation. Fluorescence spectra and/or steady-state anisotropies were measured in various solvents and in DMPC liposomes. Kinetics for the reversible DB-67 lactone ring-opening in the presence and absence of DMPC liposomes were determined by HPLC with fluorescence detection. During the entire simulation time both DB-67 and DB-67-AB were located on the bilayer membrane near the polar ester groups of DMPC. The average depth of penetration for DB-67 and DB-67-AB was similar (12.4-13.2 A) with the prodrug's protonated amino group strongly solvated by surface water and lipid phosphate groups. Binding and fluorescence experiments revealed only a modest reduction in the binding affinity upon attachment of the ionized 4-aminobutyrate group onto DB-67. The binding microenvironment polarity resembles that of a polar solvent such as EtOH and DMSO. Kinetics experiments confirmed that DB-67 lactone hydrolysis is inhibited in the presence of DMPC liposomes, consistent with the reduced exposure of its lactone ring to water, as observed in the simulations. Both bound DB-67 and bound DB-67-AB have nonrandom orientations and reduced mobility in the membrane, especially for diffusion normal to the bilayer surface, and rotational relaxation, both of which are > or =2 orders of magnitude slower than in bulk water. MD simulations correctly predicted the high binding affinities for DB-67-AB to DMPC bilayers, protection of bound DB-67 toward lactone hydrolysis, and the lack of a substantial reduction in binding for the 20(S)-4-aminobutyrate prodrug of DB-67.

Molecular dynamics simulations and experimental studies of binding and mobility of 7-tert-butyldimethylsilyl-10-hydroxycamptothecin and its 20(S)-4-aminobutyrate ester in DMPC membranes. Publishing Authors By Initials

TX Xiang,ZQ Jiang,L Song,BD Anderson,

For similar organic chemicals: organosilicon compounds research abstracts see: organic chemicals: organosilicon compounds research

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Molecular dynamics simulations and experimental studies of binding and mobility of 7-tert-butyldimethylsilyl-10-hydroxycamptothecin and its 20(S)-4-aminobutyrate ester in DMPC membranes. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular pharmaceutics

VOLUME: 3

Page Numbers: 589-600

Journal Abbreviation: Mol. Pharm.

ISSN: 1543-8384

DAY: 3

MONTH: 12

YEAR: 2007

Molecular dynamics simulations and experimental studies of binding and mobility of 7-tert-butyldimethylsilyl-10-hydroxycamptothecin and its 20(S)-4-aminobutyrate ester in DMPC membranes. Information

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LANGUAGE: eng

NlmUniqueID: 101197791

Molecular dynamics simulations and experimental studies of binding and mobility of 7-tert-butyldimethylsilyl-10-hydroxycamptothecin and its 20(S)-4-aminobutyrate ester in DMPC membranes. Keywords Mesh Terms:

KEYWORDS: Organosilicon Compounds

MESH TERMS: metabolism

Chemical & Substance for Abstract: Molecular dynamics simulations and experimental studies of binding and mobility of 7-tert-butyldimethylsilyl-10-hydroxycamptothecin and its 20(S)-4-aminobutyrate ester in DMPC membranes. Information

Substance Name: Camptothecin

Registry Number: 7689-03-4

Grant and Affiliation Information for Molecular dynamics simulations and experimental studies of binding and mobility of 7-tert-butyldimethylsilyl-10-hydroxycamptothecin and its 20(S)-4-aminobutyrate ester in DMPC membranes.

AFFILIATION: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40506, USA.

Country: United States

AGENCY: United States NCI

GRANT: R01 CA87061-03

ACRONYM: CA

MEDLINETA: Mol Pharm

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