(448d) Computational Molecular Design of Drug Delivery Vehicles for Anti-HIV Microbicides

The goal of this research is to develop a new mechanism for the prevention of HIV/AIDS that will be more readily accessible to women in developing countries. Microbicides ?vaginally-delivered anti-HIV formulations ? are a promising new solution. However, applying microbicides requires a delivery vehicle (e.g. gel or cream), which is usually polymeric. A systematic framework is needed to design these vehicles, such that the molecular structure can be tailored to meet a set of specific property requirements. Computational Molecular Design (CMD) provides a methodology to address this problem. To apply CMD, Quantitative Structure-Property Relationships (QSPRs) are developed and validated to relate the structure of potential delivery vehicles to their physicochemical properties. QSPRs are created using regression models to relate topological indices (a quantitative representation of the structure) to measured property values. Physical property data for 18 different polymeric liquids have been collected at different concentrations and average chain lengths. The six physicochemical properties considered are power-law consistency, shear-thinning index, storage modulus, loss modulus, loss tangent, and work of compression. Correlations are generated which relate the structures of the 18 different polymeric liquids to these measured property data, and are cross-validated statistically and via experiments. The completed property prediction model is then incorporated within an MINLP formulation, which can then be solved for local optima which correspond to structures possessing values for physical properties which are similar to the target values. Examples are provided which demonstrate the design of novel polymeric vehicle structures for the application of microbicides.