Interaction of Camptothecin with Model Cellular Membranes.
J Chem Theory Comput
; 16(5): 3373-3384, 2020 May 12.
Article
em En
| MEDLINE
| ID: mdl-32126167
ABSTRACT
Accurate and efficient prediction of drug partitioning in model membranes is of significant interest to the pharmaceutical industry. Herein, we utilize advanced sampling methods, specifically, the adaptive biasing force methodology to calculate the potential of mean force for a model hydrophobic anticancer drug, camptothecin (CPT), across three model interfaces. We consider an octanol bilayer, a thick octanol/water interface, and a model 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/water interface. We characterize the enthalpic and entropic contributions of the drug to the potential of mean force. We show that the rotational entropy of the drug is inversely related to the probability of hydrogen bond formation of the drug with the POPC membrane. In addition, in long-time microsecond simulations of a high concentration of CPT above the POPC membrane, we show that strong drug-drug aromatic interactions shift the spatial orientation of the drug with the membrane. Stacks of hydrophobic drugs form, allowing penetration of the drug just under the POPC head groups. These results imply that inhomogeneous membrane models need to take into account the effect of drug aggregation on the membrane environment.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Camptotecina
/
Membrana Celular
/
Antineoplásicos Fitogênicos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
J Chem Theory Comput
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos