Modelling and study of cyclosporin A and related compounds in complexes with a Trypanosoma cruzi cyclophilin

Cyclophilins (CyPs) are enzymes involved in protein folding, catalyzing the isomerisation of peptidyl prolyl bonds in proteins and peptides between the cis- and trans-conformations. They are also the major cellular target for the immunosuppressive drug Cyclosporin A (CsA). In Trypanosoma cruzi, the most abundantly expressed CyP is an isoform of 19 kDa, TcCyP19, in which the enzymatic activity is inhibited by CsA. Among a reported set of CsA analogues, two non-immunosuppressive compounds, H-7-94 and F-7-62, proved to be the best inhibitors of TcCyP19 enzymatic activity as well as the most efficient trypanocidal drugs.With the objective of analysing, at the molecular level, how the structural differences between the three above-mentioned inhibitors justify their different inhibitory activity on TcCyP19, three-dimensional molecular modelling structures were generated to computationally simulate behaviours and interactions. An energy-minimized model of each binary complex in water with ions was obtained. These models were then used as starting point for molecular dynamic simulations, performed with GROMOS96 program.With the resulting set of co-ordinates and energies, a comparison of the interaction between CsA and both CsA analogues in T. cruzi and human cyclophilins were performed. Within the different magnitudes analysed, the total potential complex energy exhibited the best correlation with the experimental data.The results obtained in this study support the use of this methodology when designing new lead inhibitor compounds.