Protein Modeling and Structure-Based Drug Design

Abstract

Structure-based drug design focuses on the search, design, and optimization of a small molecule that fits well into the binding pocket of a target protein to form energetically favorable interactions. Initially, a detailed analysis of the protein is performed. All information about its structure and that of related proteins are evaluated. Next, the properties of the binding pocket are thoroughly explored, and areas are sought where an optimal binding is to be expected. Experimental techniques as well as computer methods are employed to discover a lead structure from a screening library (Chap. 7, “Screening Technologies for Lead Structure Discovery”). Alternatively, approaches are also applied that begin with a small molecular “seed” in the binding pocket, which is then allowed to “grow” to a potent ligand by using a stepwise iterative design. This approach uses fast docking techniques that propose relevant binding geometries. The geometries are evaluated with a scoring function, which estimates whether they are energetically favorable.