Study of interaction energies between the PAMAM dendrimer and nonsteroidal anti-inflammatory drug using a distributed computational strategy and experimental analysis by ESI-MS/MS.
The structure of a dendrimer exhibits a large number of internal and superficial cavities, which can be exploited, to capture and deliver small organic molecules, enabling their use in drug delivery. Structure-based modeling and quantum mechanical studies can be used to accurately understand the interactions between functionalized dendrimers and molecules of pharmaceutical and industrial interest. In this study, we implemented a Metropolis Monte Carlo algorithm to calculate the interaction energy of dendrimer-drug complexes, which can be used for in silico prediction of dendrimer-drug affinity. Initially, a large-scale sampling of different dendrimer-drug conformations was generated using Euler angles. Then, each conformation was distributed on different nodes of a GRID computational system, where its interaction energy was calculated by semiempirical quantum mechanical methods. These energy calculations were performed for four different nonsteroidal anti-inflammatory drugs, each showing different affinities for the PAMAM-G4 dendrimer. The affinities were also characterized experimentally by using Cooks' kinetic method to calculate PAMAM-drug dissociation constants. The quantitative structure-activity relationship between the interaction energies and dissociation constants showed statistical correlations with r(2) > 0.9.
Nanobiotechnology Division at University of Talca, Fraunhofer Chile Research Foundation - Center for Systems Biotechnology, FCR-CSB, Talca, Chile.
Fabián
F
Avila-Salas
Claudia
C
Sandoval
Julio
J
Caballero
Sergio
S
Guiñez-Molinos
Leonardo S
LS
Santos
Raúl E
RE
Cachau
Fernando D
FD
González-Nilo
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry*; D003198:Computer Simulation; D050091:Dendrimers / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D008958:Models, Molecular; D009010:Monte Carlo Method; D009757:Nylons / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D013816:Thermodynamics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D050091:Dendrimers; D004337:Drug Carriers; D009757:Nylons; C104700:PAMAM Starburst; C520550:PAMAM-G4