Neuropharmacology in Flux: Molecular modeling tools for understanding protein conformational shifts in Alzheimer’s Disease and related disorders

Abstract

Several years of exciting discoveries finally promise to break a decades-old impasse in the treatment of many of society’s most debilitating neurological disorders, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease. These breakthroughs are beginning to paint a detailed picture of the causes and effects associated with polynucleotide-associating domains of key central nervous system proteins that misfold into energetically favored physiologically dysfunctional forms. Unfortunately, the paradigm differs so dramatically from conventional pharmacological scenarios that the translation of fundamental molecular concepts to practical therapeutic design is far more challenging than merely identifying a novel enzymatic or cellular target. This chapter seeks to grasp the fundamental physiological issues that cause neuropathies and maps out the ways in which molecular docking and molecular dynamics simulations can be brought to bear in formulating testable hypotheses that can form a basis for the systematic formulation of a new generation of medicines.