Computational studies of HIV-1 RT and quinone oxidoreductase: Interaction, activity, and mechanism

HIV-1 reverse transcriptase (HIV-1 RT) plays an important role in the duplication of HIV-1. It has been a target in the development of drugs to inhibit HIV and cure AIDS. Two categories of inhibitors targeting this enzyme have been developed. One is a nucleoside analogue, which can be synthesized into DNA as a nucleoside to stop the strand further extension. The other is a non-nucleoside RT inhibitor (NNRTI), which binds in a hydrophobic pocket located in the palm area of p66 subdomain of RT. Docking, free energy of binding (FEB) and M.D simulations are computational ways to explore the binding structure, binding affinity and interaction of ligand/receptor. In the work, several computational approaches were used to explore the NNRTIs binding in RT and quinones binding in QR1.; First nevirapine was docked back into its crystal coordinates to validate the docking simulation on the reproduction of binding structure. The docking results show that the docking approach can reproduce crystal structures well in terms of RMSD of ligand between docked and crystal structure. The same docking simulation was used to dock neotripterifordin and its derivatives to HIV-1 RT. The results show that these NNRTIs dock in a similar position and orientation as known inhibitors. In addition, we observe a linear correlation between the calculated energy and EC₅₀ for the inhibitors. Also, hydrogen bonds were observed formed among ligand, receptor, and waters. Two docking simulations from two difference levels of resolution (2.9 Å and 2.2 Å) of crystal structures produced similar results. It indicates that a coarse resolved crystal structure can be used in docking simulation.; In addition to HIV-1 RT bio-molecular system, docking simulations were carried out to explore the binding properties of quinones in NAD(P)H/quinone acceptor oxidoreductase (QR1). QR1 protects cells from cytotoxic and neoplastic effects of quinones through two-electron reduction. Kinetic experiments, docking, and binding affinity calculations were performed on a series structurally varied quinone substrates. A good correlation between calculated and measured binding affinities from kinetic determination was obtained. The experimental and theoretical studies independently support a model in which quinones (with one to three fused aromatic rings) bind in the QR1 active site utilizing a π-stacking interaction with the isoalloxazine ring of FAD cofactor. (Abstract shortened by UMI.)...