This project concerns the non-nucleoside TIBO series of HIV-1 reverse transcriptase (RT) inhibitors. The first part, almost completed, is a refinement process of HIV-1 RT TIBO inhibitors in the development of more efficient drugs which inhibit the progression of HIV infection. This process involves novel methods that work on different levels of accuracy for estimating the relative free energy of binding of a series of inhibitors. Since much experimental data is available for the TIBO inhibitors, they are also suitable for an evaluation of the computational methods. The general refinement scheme is to suggest modifications of lead inhibitors and rank the modified inhibitors in terms of their binding free energy. Finally, the most accurate method - """"""""full"""""""" free energy calculations - is performed on the highest ranked modified inhibitors to reveal whether the suggested modification really improved the inhibitor binding. The goal of the second part of the project is to gain a deeper understanding of structural and dynamic reasons for drug resistant mutations with the use of molecular dynamics (MD) simulations and free energy perturbations. Initially, we will focus this study on the Tyr181Cys mutation in HIV-1 RT since this mutation has a marked difference in resistance towards the two derivatives 8 Cl- and 9 Cl-TIBO.
Our aim i s to study this difference in terms of different contacts with the protein, different compensating contacts in the mutant RT, and possible entropic effects, such as differences in inhibitor or protein mobilities. Free energy perturbations will then confirm the differences in drug resistance in terms of different free energy of binding the two inhibitors. From these insights, we might also get ideas on how to design an inhibitor, which is a potent for wild type HIV-1 RT as well as for the Tyr181Cys mutated form. This research is heavily dependent on the computer graphics facilities provided by the Computer Graphics Laboratory. A continuous graphical inspection of structural changes during the simulations and during the perturbations is essential to make correct decisions on how to continue the simulations/perturbations.
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