| This thesis comprises two parts. The first, Chapters 2–4, describes the development and improvement of models for the prediction of noncovalent binding affinities. The second, Chapter 5; concerns the discovery of competitive inhibitors of Rev-RRE binding in HIV as a first step toward a new class of therapeutics for AIDS.; In the first project, new methods for molecular conformational search and for the calculation of molecular configuration integrals were developed. Both methods use the CHARMM empirical force field, implicit solvent models, and normal mode analysis in internal bond-angle-torsion coordinates. The conformational search method, Tork, focuses on a key subset of torsional coordinates to identify vibrational modes of a molecular system and distorts the system along these modes to move to new energy minima. The free energy calculation method for computing the configuration integral in a single energy well—the harmonic approximation with mode scanning (HA/MS)—uses the harmonic approximation with finite integration ranges, along with Mode Scanning; a fast correction for anharmonicity. The method is shown to be accurate via comparisons with analytic results and, where these are unavailable, with highly detailed Monte Carlo integrations. Both Tork and HA/MS are highly efficient for cyclic, acyclic, and macrocyclic molecules and also host-guest complexes. Binding free energies are computed by using Tork to find low-energy conformations and the HA/MS method to compute chemical potentials. Comparisons with experiment support the validity of the theory and the methods, and also indicate that the energy models are reasonable, although not perfect. These studies also allow analysis of the continuum solvation models used. The calculations are fast enough to be used in practical applications, and should be of considerable value as a tool for improving force fields and solvent models.; The second part of the thesis describes the application of molecular docking and chemical informatics to the discovery of new ligands for the RRE segment of RNA from the AIDS virus. This work has identified proflavine and other acridine-derived molecules as examples of a new class of lead compounds for pharmaceutical development towards novel RNA-targeted antiviral drugs. |
