UC Irvine

The growing cost of new drugs has become a concern for the biopharmaceutical industry, which depends on innovation to sustain itself. As a result, computational methods have been increasingly implemented into the drug design workflow in an effort to reduce the cost of finding new lead candidates. Here, we focus on several applications and the development of the Molecular Mechanics Poisson-Boltzmann (MMPBSA) method for its use in rational drug design efforts. Chapter 1 demonstrates the use of computational methods in the analysis and design of anti-A?? antibodies for their prospective use in the treatment of Alzheimer’s Disease. Chapter 2 applies our single dielectric implicit membrane model to MMPBSA calculations of the membrane-bound human purinergic platelet receptor, a prominent target for treating myocardial infarction and stroke. Chapter 3 documents the development, implementation, and application of a new heterogeneous dielectric implicit membrane model for MMPBSA calculations. Chapter 4 shows the validity of our method to parameterize the non-polar terms in a depth dependent manner within our implicit membrane model. This work as a whole demonstrates both the present utility and ongoing improvement of the MMPBSA method for its use in the rational design of new drugs.