NSTI BioNano 2010

Affinity calculations between PAMAM dendrimer and non-steroidal anti-inflammatory drugs using computational chemistry and distributed computing methodologies

C. Sandoval, F. Ávi la Sala, F.D. Gonzalez-Nilo, R.E. Cachau
Universidad de Talca, CL

Keywords: PAMAM dendrimer, non-steroidal anti-inflammatory drugs

Abstract:

The drug delivery systems using dendrimers as carriers appears as one of the applications in nanotechnology with greater projection [1], mainly due to the great impact that these emerging techniques have on human health (nanomedicine). The use of these technologies will allow reducing the dose and increase the effectiveness of drugs that interact with these nanoparticles [2]. Therefore, the knowledge of electrostatics and Van der Waals interactions involved in the drugs attachment and/or encapsulation is critical for the development of these systems [3] (see Figure 1). Currently, one of the main challenges in this field is to predict the affinity of a dendrimer to a specific drug. Within this area, the evaluation of interaction energies between dendrimers and drugs can be one way of validating these systems. From this arises the need to develop and implement efficient computational chemistry tools that enable advanced structural characterization of intermolecular interactions at the atomic scale (nanoinformatics), what would be a good indicator of the affinity and other specific properties of different drugs in the presence of a dendrimer. This work proposes a fast and efficient computational methodology to calculate the interaction energies between pairs of molecules (dendrimer-drugs) generated through a Monte Carlo algorithm [4]. The calculations of interaction energies of each pair of conformations were performed using semi-empirical quantum mechanical methods (PM6). To reduce the computational cost that implies the use of these methods and optimize the calculations has been implemented a MPI program (Message Passing Interface) written in base to programming model Master/Slave that distributes each pair of conformations in the different nodes of a PC cluster, where the energy calculations are performed. This strategy was applied to a series of four non-steroidal anti-inflammatory drugs (NSAIDs) (see Figure 1), which have different levels of affinity with respect to the PAMAM-G5 dendrimer. The experimental rate constants for competitive dissociation (ln k1/k2) obtained with the Cook’s kinetic method (CKM) were used to experimentally characterize the affinity between PAMAM and the four NSAIDs [5]. The quantitative structure-activity relationship between the average of total interaction energies and the experimental constants was highly satisfactory, showing a statistical correlation with r2 > 0,9 (See Figure 2). For the other hand, the Radial Distribution Function g(r), between carbon atoms of monomeric unit of the dendrimer and carbon atoms from the specific drug (excepting the carbon atoms from the carboxyls groups) was obtained to observe the orientation of the NSAIDs respect to the aliphatic segment of monomer of PAMAM dendrimer (see Figure 3-4).
 
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