Molecular modelling investigations of chloramphenicol supramolecular systems

A. ZOPPI; M. QUEVEDO; M. LONGHI; V. AIASSA

Cordoba

Congreso; 3a Reunión Internacional de Ciencias Farmacéuticas; 2014

Universidad Nacional de Córdoba

Molecular modeling (MM) combining theoretical methods and computing techniques are currently used to aid the study of molecular interactions involved in supramolecular systems of pharmaceutical interest. In this work, MM was applied to investigate the interaction between chloramphenicol (CP) and β-cyclodextrin (βCD) in presence of several aminoacids (AA): [glycine (GLI), L-cysteine (CYS) or N-acetyl-L-cysteine (NAC)]. CP structure was subjected to conformational analyses, after which complexes with βCD were predicted by molecular docking using the software designed by Open Eye Inc. (FRED, OMEGA). The complex was afterwards subjected to molecular dynamics (MD) simulations, confirming the inclusion of CP within the βCD hydrophobic cavity, which is stabilized by electrostatic (-30.6 kcal/mol) and van der Waals (-23 kcal/mol) interactions. The electrostatic stabilization is originated in hydrogen bond interactions between hydroxyls of CP and hydroxyls located in the wide rim of βCD. The binary complex conformation was afterwards used to dock GLI, CYS and NAC (in ternary complexes). When the three dimensional structure of the ternary complexes was analyzed, it was observed that the three AA are bound on the wide rim of βCD, as intercalators between CP and βCD and establishing hydrogen bond interactions with CP and βCD. A competition by native hydrogen bonds between CP and βCD was observed in the binary complex, which may originate the experimentally observed lowered affinity of CP to βCD in the ternary systems if compared to the binary counterpart. To further confirm the inclusion behavior, MM studies were also supported by 1D 1H and 2D ROESY NMR analyses, with results being in agreement. Based on the presented results, the three dimensional structures of the CP:βCD:AA complexes were elucidated and analyzed, with good agreement between MM studies and experimental observations. MM studies arise as a powerful technique to further select the suitable AA for CP:βCD complexes.