title: Computationally efficient methodology for atomic-level characterization of dendrimer-drug complexes: a comparison of amine- and acetyl-terminated PAMAM.
abstract: PAMAM dendrimers have been widely studied as a novel means for controlled drug delivery; however, computational study of dendrimer-drug complexation is made difficult by the conformational flexibility of dendrimers and the nonspecific nature of the dendrimer-drug interactions. Conventional protocols for studying drug binding have been designed primarily for protein substrates, and, therefore, there is a need to establish new protocols to deal with the unique aspects of dendrimers. In this work, we generate cavities in generation-5 polyamidoamine (PAMAM) dendrimers at selected distances from the center of mass of the dendrimer for the insertion of the model drug: dexamethasone 21-phosphate or Dp21. The complexes are then allowed to equilibrate with distance between centers of mass of the drug and dendrimers confined to selected ranges; the free energy of complexation is estimated by the MM-GBSA (MM, molecular mechanics; GB, generalized Born; SA, surface area) method. For both amine- and modified acetyl-terminated PAMAM at both low and neutral pH, the most favorable free energy of complexation is associated with Dp21 at distance of 15-20 Å from the center of mass of the dendrimer and that smaller or larger distances yield considerably weaker affinity. In agreement with experimental results, we find acetyl-terminated PAMAM at neutral pH to form the least stable complex with Dp21. The greatest affinity is seen in the case of acetyl-terminated PAMAM at low pH, which appears to be due a complex balance of different contributions, which cannot be attributed to electrostatics, van der Waals interactions, hydrogen bonds, or charge-charge interactions alone.
authors: Center for Bioinformatics and Molecular Simulation, Universidad de Talca, 2 norte 685, Talca-Chile.
authors: Ariela
authors: A
authors: Vergara-Jaque
authors: Jeffrey
authors: J
authors: Comer
authors: Luis
authors: L
authors: Monsalve
authors: Fernando D
authors: FD
authors: González-Nilo
authors: Claudia
authors: C
authors: Sandoval
mesh_terms: D000588:Amines / Q000737:chemistry*; D050091:Dendrimers / Q000737:chemistry*; D003907:Dexamethasone / Q000031:analogs & derivatives* / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011073:Polyamines / Q000737:chemistry*; D012997:Solvents / Q000737:chemistry; D013499:Surface Properties; D013816:Thermodynamics
chemical_list: D000588:Amines; D050091:Dendrimers; C104700:PAMAM Starburst; C531249:Poly(amidoamine); D011073:Polyamines; D012997:Solvents; C004180:dexamethasone 21-phosphate; D003907:Dexamethasone