Estudio computacional de agregados de anfotericina b con moléculas hidrófobas con potencial uso para modificación de copolímeros empleados en la encapsulación de anfotericina

Abstract

The present work is a contribution to a macro project in which the experimental results together with the computational results intend to propose new and / or improvement of the methods currently used for the encapsulation of amphotericin B (AmfB) to implement it as a pathway treatment. oral and possibly domiciliary and thus have an alternative to its intravenous application, which is costly and requires assistance to the hospital. In this work, a series of hydrophobic compounds with potential use for the modification of the copolymers that encapsulate AmfB was evaluated in a computational way, using methods of the Density Functional Theory (DFT), reducing their secondary effects as adverse responses that are may present in the human body. This is an example of the use of computational chemistry in topics related to the branch of medicine in terms of the possibility of proposing possible restructuring of materials from computational modeling studies before investing in reagents, also reducing exposure to different chemical substances. For this research, the starting geometries of the hydrophobic compounds (Dodecanol, Resorcinol, ɣ-Cyclodextrin, Cholesterol, 1,2-diasteroyl-sn-glycero-3-phosphathanolamine (DSPE)) as well as AmfB from structures reported in databases approved by the scientific community and / or from the determination of possible conformers using the Gaussview viewer in the molecule drawing option. Subsequently, its geometric optimization was carried out using the base 6-311G (d, p) and the theory level M06-2X. All the electronic structure calculations (optimization, frequencies, point energies, atomic charges, etc.) were carried out in the Gaussian 09 software. Using the same theoretical approach, the different dimers postulated to interact between our study molecule the AmfB and the previously optimized hydrophobic compounds. 19 dimers were optimized and verified as stable (zero imaginary frequencies): 6 dimers like dodecanol (1 to 6), 6 dimers with cholesterol (1, 2, 3, 4, 7, and 8), 4 dimers with resorcinol (1, 2, 6 and 8), 2 dimers with DSPE (1 and 4) and 1 dimer with γ-cyclodextrin (4). Note that the numbers in parentheses indicate the enumeration used to differentiate the dimers, thus, for example, 4 for γ-cyclodextrin indicates that it is the dimer named: 4-gamma-amfB. No relationship was found in the polarity of the hydrophobic compounds compared with the polarity of the AmfB (dipole moment) and the order of affinity obtained with energetic data. From thermodynamic data, the following order of affinity between AmfB and the different hydrophobic compounds could be determined:

Amphotericin B - 1,2-distearoyl-sn-glycero-3-phosphateethanolamine (DSPE) Amphotericin B - ɣ- cyclodextrin Amphotericin B - Cholesterol Amphotericin B - Resorcinol Amphotericin B - Dodecanol