Association of the anti-tuberculosis drug rifampicin with a PAMAM dendrimer

• Published in: Journal of molecular graphics & modelling Vol. 60; pp. 34 - 42
• Main Authors: Bellini, Reinaldo G., Guimarães, Ana P., Pacheco, Marco A.C., Dias, Douglas M., Furtado, Vanessa R., de Alencastro, Ricardo B., Horta, Bruno A.C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2015
• Subjects: Antitubercular Agents - administration & dosage; Antitubercular Agents - chemistry; Antitubercular Agents - metabolism; Computer simulation; Dendrimer; Dendrimers; Dendrimers - chemistry; Dendrimers - metabolism; Derivatives; Drug Carriers - chemistry; Drug Carriers - metabolism; Drug delivery; Drug Stability; Drugs; Hydrogen-Ion Concentration; Molecular Docking Simulation; Molecular dynamics; Molecular Dynamics Simulation; Molecular Structure; Mycobacterium; PAMAM; Polyamines - chemistry; Polyamines - metabolism; Rifampicin; Rifampin - administration & dosage; Rifampin - chemistry; Rifampin - metabolism; Simulation; Solubility; Stability; Switches; Water; Molecular dynamics; Dendrimer; Drug delivery; Rifampicin; Computer simulation; PAMAM
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2015.05.012

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•The association of the drug rifampicin (RIF) with a G4-PAMAM dendrimer was studied.•The maximum drug load was determined to be around 20 RIF per G4-PAMAM.•Under neutral pH, the RIF-PAMAM complex was observed to be stable.•Under acidic pH, a triggered simultaneous drug release was observed.
The association of the anti-tuberculosis drug rifampicin (RIF) with a 4th-generation poly(amidoamine) (G4-PAMAM) dendrimer was investigated by means of molecular dynamics simulations. The RIF load capacity was estimated to be around 20 RIF per G4-PAMAM at neutral pH. The complex formed by 20 RIF molecules and the dendrimer (RIF20-PAMAM) was subjected to 100ns molecular dynamics (MD) simulations at two different pH conditions (neutral and acidic). The complex was found to be significantly more stable in the simulation at neutral pH compared to the simulation at low pH in which the RIF molecules were rapidly and almost simultaneously expelled to the solvent bulk. The high stability of the RIF-PAMAM complex under physiological pH and the rapid release of RIF molecules under acidic medium provide an interesting switch for drug targeting since the Mycobacterium resides within acidic domains of the macrophage. Altogether, these results suggest that, at least in terms of stability and pH-dependent release, PAMAM-like dendrimers may be considered suitable drug delivery systems for RIF and derivatives.